Therapeutic agents

ABSTRACT

The invention provides compounds of formula I ##STR1## and pharmaceutically acceptable salts thereof; wherein R 50  is hydrogen or C 1-4  alkyl, A 51  is oxygen, sulphur or a group of the formula --NR 52  -- wherein R 52  is hydrogen or C 1-4  alkyl; A 50  comprises i) a mono or bicyclic aromatic ring optionally containing one or more nitrogen, oxygen or sulphur atoms, ii) a cycloalkendiyl group, or iii) an acyclic bridging group having a chain of one, two or three atoms between the cyclobutenedione group and X 50 , said chain being a chain of one or two carbon atoms or a chain of one carbon atom and one or more nitrogen, oxygen or sulphur atoms or iv) a bond; X 50  is either a bond or a spacer group providing a chain between A 50  and B 50  of one or two atoms length; B 50  is a mono or bicyclic aromatic-ring optionally containing one or more nitrogen, oxygen or sulphur atoms; r is an integer from 1 to 6; and Het is a ring system optionally containing one or more nitrogen, oxygen or sulphur atoms or is a phosphonate, phosphinate or amine derivative (wherein each of A 50 , X 50 , B 50  and Her are optionally substituted). 
     The compounds have angiotensin II antagonist activity and are useful in the treatment of cardiovascular disorders such as hypertension.

This application is a 371 of PCT/EP93/01774 filed Jul. 3, 1993.

The present invention relates to novel therapeutic agents and, inparticular, to novel substituted cyclobut-3-ene-1,2-diones, to processesfor their preparation, to pharmaceutical compositions containing themand to their therapeutic activity in the treatment of cardiovasculardiseases.

Angiotensin II is a key mediator of the reninangiotensin system. It isknown that angiotensin II is an arterial vasconstrictor that exerts itsaction by interacting with specific receptors on cell membranes.Recently, several non-peptide compounds have been reported asangiotensin II antagonists and as useful antihypertensive agents.

The present invention provides compounds of formula I ##STR2## andpharmaceutically acceptable sales thereof; wherein R₅₀ is hydrogen orC₁₋₄ alkyl, A₅₁ is oxygen, sulphur or a group of the formula --NR₅₂ --wherein R₅₂ is hydrogen or C₁₋₄ alkyl; A₅₀ comprises i) a mono orbicyclic aromatic ring optionally containing one or more nitrogen,oxygen or sulphur atoms, ii) a cycloalkendiyl group, iii) an acyclicbridging group having a chain of one, two or three atoms between thecyclobutenedione group and X₅₀, said chain being a chain of one or twocarbon atoms or a chain of one carbon atom and one or more nitrogen,oxygen or sulphur atoms or iv) a bond; X₅₀ is either a bond or a spacergroup providing a chain between A₅₀ and B₅₀ of one or two atoms length;B₅₀ is a mono or bicyclic aromatic ring optionally containing one ormore nitrogen, oxygen or sulphur atoms; r is an integer from 1 to 6; andHet is a ring system optionally containing one or more nitrogen, oxygenor sulphur atoms or is a phosphonate, phosphinate or amine derivative(wherein each of A₅₀, X₅₀, B₅₀ and Het are optionally substituted).

Preferably, A₅₀ is a group selected from the groups represented by (i)to (xii) below (wherein in each case Z₅₀ is a bond to X₅₀ and the otherfree valency is connected to the cyclobutenedione group). ##STR3##wherein R₇₀ and R₇₁ are each independently hydrogen, hydroxy, alkyl(optionally substituted by halo, C₃₋₈ cycloalkyl or phenyl), C₃₋₁₂cycloalkyl or phenyl (both optionally substituted by halo, C₁₋₆ alkyl orC₁₋₆ alkoxy) or R₇₀ and R₇₁ together complete a 3 to 7 memberedcarbocycle (optionally substituted by one or two C₁₋₆ alkyl, C₁₋₆alkoxy, phenyl, hydroxy or halo groups); ##STR4## wherein A₆₀ isnitrogen or methine; A₆₁ is imino, oxygen or sulphur and either R₈₀ andR₈₁ are each independently hydrogen, halo, fluoro, nitro, cyano, alkylC₂₋₁₀ (preferably C₂₋₄)alkenyl, alkylthio, mono-, di- or trihalo-(C₁₋₆alkyl), hydroxyalkyl, oxoalkyl, carboxy or esterified carboxy, or, whenR₈₀ and R₈₁ are on adjacent carbon atoms, R₈₀ and R₈₁ together may be1,3-butadienylene thereby completing a fused aromatic ring; ##STR5##wherein R₉₀ to R₉₇ are each independently hydrogen, halo, fluoro, nitro,amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄alkyl, C₁₋₄ alkoxy or a group of the formula --SO₂ NHR₉₈ (wherein R₉₈ ishydrogen, C₁₋₅ alkyl, aryl or arylmethyl); ##STR6## wherein --A₇₀ --A₇₁--A₇₂ --A₇₃ -- is a group of formula --NC(R₁₀₀)C(R₁₀₁)C(R₁₀₂)--,--C(R₁₀₀)NC(R₁₀₁)C(R₁₀₂)--, --C(R₁₀₀)C(R₁₀₁)NC(R₁₀₂)--,--C(R₁₀₀)C(R₁₀₁)C(R₁₀₂)N--, --NC(R₁₀₀)NC(R₁₀₁)--, --C(R₁₀₀)NC(R₁₀₁)N--,--NNC(R₁₀₀)C(R₁₀₁)--, --C(R₁₀₀)NNC(R₁₀₁)--, --C(R₁₀₀)C(R₁₀₁)NN--,--NC(R₁₀₀)C(R₁₀₁)N--,--C(R₁₀₀)C(R₁₀₁)C(O)N(R₁₀₃)----C(R₁₀₀)C(R₁₀₁)N(R.sub.103)C(O)--,--C(O)N(R₁₀₃)C(R₁₀₀)C(R₁₀₁)--, --N(R₁₀₃)C(O)C(R₁₀₀)C(R₁₀₁)--,--C(O)N(R₁₀₃)C(R₁₀₀)N--, --C(R₁₀₀)NC(O)N(R₁₀₃)--,--N(R₁₀₃)C(O)NC(R₁₀₀)--, --NC(R₁₀₀)N(R₁₀₃)C(O)--,--C(O)N(R₁₀₃)NC(R₁₀₀)-- or --C(R₁₀₀)NN(R₁₀₃)C(O)--; wherein R₁₀₀ to R₁₀₂are each independently hydrogen, halo, fluoro, nitro, amino, C₁₋₄alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄alkoxy or a group of the formula SO₂ NHR₁₀₄ (wherein R₁₀₄ is hydrogen,C₁₋₆ alkyl, aryl, arylmethyl or a group of formula --CH₂ OC(O)CH₃) or,when two of R₁₀₀, R₁₀₁ and R₁₀₂ are bonded to adjacent carbon atoms,they may be joined to form a fused phenyl or naphthyl ring; and R₁₀₃ ishydrogen, C₁₋₄ alkyl, phenyl or phenylmethyl (in which the phenyl orphenylmethyl is optionally substituted with one or two substituentsselected from halo, fluoro, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl,amino, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino or a group of formula --CO₂R₁₀₄ (wherein R₁₀₄ is as defined above)); ##STR7## wherein --A₈₀ --A₈₁--A₈₂ --A₈₃ -- is a group of formula --Y₅₀ --C(R₁₁₀)C(R₁₁₁)C(Z₅₂)--,--C(R₁₁₀)Y₅₀ C(R₁₁₁)C(Z₅₂)--, --C(R₁₁₀)C(R₁₁₁)Y₅₀ C(Z₅₂)--, --Y₅₀C(R₁₁₀)C(Z₅₂)C(R₁₁₁)--, --C(R₁₁₀)Y₅₀ C(Z₅₀)C(R₁₁₁)-- or--C(R₁₁₀)C(R₁₁₁)C(Z₅₂)Y₅₀ --, wherein Y₅₀ is oxygen, sulphur, sulphinylor sulphonyl; R₁₁₀ and R₁₁₁ are each independently hydrogen, halo,fluoro, nitro, amino, formyl, C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino,trifluoromethyl, C₁₋₇ alkyl, C₁₋₆ alkoxy, C₃₋₇ cycloalkyl, or a group offormula --SO₂ NHR₁₁₂, --(CH₂)_(c) O(CH₂)_(d) CH₃, --(CH₂)_(d) O(CH₂)_(d)CH₃, --(CH₂)N(R₁₁₂)₂, --CH(OR₁₁₂)(C₁₋₇ alkyl), --CO₂ R₁₁₂, --CH═CHR₁₁₂,--CH₂ CR₁₁₂ ═C(R₁₁₂)₂, --(CH₂)_(e) NHC(O)R₁₁₂ --(C₁₋₄)alkylaryl or--CH(R₁₁₂)₂ (wherein R₁₁₂ is hydrogen, C₁₋₆ alkyl, arylmethyl or aryl, cis an integer from about 1 to 3, d is an integer from 1 to 5 and e is 0or an integer from 1 to 2) or, when R₁₁₀ and R₁₁₁ are bound to adjacentcarbon atoms, they may be joined to form a phenyl or naphthyl ring; andwherein Z₅₂ represents the "other" free valency referred to above;##STR8## wherein A₉₀ is a bond, oxygen, sulphur, sulphinyl, sulphonyl,methylene or a group of the formula --NR₁₂₂ -- (wherein R₁₂₂ ishydrogen, C₁₋₆ alkyl, aryl, aryl(C₂₋₇ )alkylcarbonyl,(C₁₋₆)alkylcarbonyl, [(C₂₋₅)alkenyl]methylene, [(C₂₋₅)alkynyl]methyleneor arylmethylene); and R₁₂₀ and R₁₂₁ are each independently hydrogen,C₁₋₆ alkyl (optionally substituted with aryl or C₃₋₇ cycloalkyl), aryl(optionally substituted with up to five substituents selected from halo,fluoro, C₁₋₆ alkyl, (C₂₋₅ alkenyl)methylene, (C₂₋₅ alkynyl)methylene,C₁₋₅ alkoxy, C₁₋₅ alkylthio, nitro, trifluoromethyl, hydroxy, nitro, ora group of formula --CO₂ R₁₂₃ (wherein R₁₂₃ is hydrogen, C₁₋₆ alkyl,aryl or arylmethylene)), or aryl-(C₁₋₂)alkyl, (optionally substitutedwith up to 5 substituents selected from halo, fluoro, C₁₋₆ alkyl, (C₂₋₅alkenyl)methylene, (C₂₋₅ alkynyl)methylene, C₁₋₅ alkoxy, C₁₋₅ alkylthio,nitro, trifluoromethyl, hydroxy or group of formula --CO₂ R₁₂₃ (whereinR₁₂₃ is defined above)), or C₃₋₇ cycloalkyl. ##STR9## wherein R₁₃₀, R₁₃₁and R₁₃₂ are each independently hydrogen, halo, fluoro, nitro, amino,C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄alkoxy or a group of the formula --SO₂ NHR₁₃₃ (wherein R₁₃₃ is hydrogen,C₁₋₅ alkyl, aryl or arylmethyl); ##STR10## wherein R₁₄₀ is hydrogen,alkyl, aryl (meaning phenyl optionally substituted with halo, fluoro,alkyl, alkoxy, alkylthio, hydroxy, alkanoyl, nitro, amino, dialkylamino,trifluoromethyl, C₃₋₇ cycloalkyl or arylalkyl); A₁₀₀ is nitrogen (whenthe dotted substituted with a group selected independently from the listprovided to define R₁₄₀ (when the dotted line is not a bond); and R₁₄₁and R₁₄₂ are each independently hydrogen, halo, fluoro, nitro, amino,C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄alkoxy or a group of formula --SO₂ NHR₁₄₃ (wherein R₁₄₃ is hydrogen,C₁₋₅ alkyl or arylmethylene); ##STR11## wherein R₁₅₀ is hydrogen, C₁₋₆alkyl, a group of formula Y₆₀ wherein Y₆₀ is phenyl or 1- or 2-naphthyl(each optionally substituted by methyl, methoxy, hydroxy, bromo, chloro,fluoro, nitro, amino, diethylamino, methylthio or sulphydryl), a groupof formula C₁₋₆ alkyl-Y₆₀ - (wherein Y₆₀ is as defined above), a groupof formula Y₆₁ (wherein Y₆₁ is a 5- or 6-membered ring or 8-, 9- or10-membered bicyclic system containing one or more heteroatoms selectedfrom nitrogen, oxygen and sulphur (including bun not limited to pyrrole,imidazole, thiophene, furan, pyridine, thiazole, indole, morpholine andisoquinoline)) optionally substituted by halo, fluoro, C₁₋₆ alkyl, C₁₋₆alkyloxy or hydroxy; or a group of formula C₁₋₆ alkyl-Y₆₁ - (wherein Y₆₁is as defined above); ##STR12## wherein A₁₁₁ is oxygen, sulphur, iminoor methylene; and if A₁₁₁ is oxygen, sulphur or imino, then A₁₁₀ is agroup of formula --CR₁₆₀ R₁₆₁ -- and if A₁₁₁ is methylene, then A₁₁₀ iseither nitrogen or a group of formula --CR₁₆₀ R₁₆₁ -- wherein R₁₆₀ andR₁₆₁ are each independently hydrogen, C₁₋₁₀ alkyl, C₃₋₁₀ alkenyl, C₃₋₁₀alkynyl, C₃₋₈ cycloalkyl, C₄₋₁₀ cycloalkylalkyl, C₅₋₁₀cycloalkylalkenyl, C₅₋₁₀ cycloalkyl alkynyl or aryl optionallysubstituted with one or two of halo, C₁₋₄ alkyl or C₁₋₄ alkoxy;##STR13## wherein b is 2, 3 or 4; or ##STR14## wherein R₁₇₁ is hydrogen,halo, fluoro, C₁₋₄ alkyl, C₁₋₄ alkoxy; and R₁₇₀ is hydrogen, halo,fluoro, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, C₁₋₄ acyloxy, carboxy(optionally esterified), phenyl, furyl or a group of formula --NHSO₂ Me,--NHSO₂ CF₃, --SO₂ NH₂ or --CONHR₁₇₂ (wherein R₁₇₂ is hydrogen, methylor benzyl).

Suitably, when X₅₀ is a spacer group it is carbonyl, oxygen, sulphur,vinylene, difluorovinylene, monofluorovinylene, ethylene,perfluoroethylene, oxymethylene, thiomethylene, or a group of formula--NR₅₃ --, --CONR₅₄ --, --NR₅₄ CO--, --NHCR₅₅ R₅₆ --, --NR₅₅ SO₂ --,--SO₂ NR₅₅ --. CR₅₅ R₅₆ NH--, --CH(OR₅₇)--, --CH(OCOR₅₈)--, or--C(NR₅₉)-- (where R₅₃ is hydrogen, C₂₋₄ acyl, C₁₋₆ alkyl, allyl, C₃₋₆cycloalkyl, phenyl or benzyl, R₅₄ is hydrogen or C₁₋₄ alkyl, R₅₅ ishydrogen, C₁₋₅ alkyl, phenyl or benzyl, R₅₆ is hydrogen or C₁₋₁₄ alkyl,R₅₇ is hydrogen, C₁₋₈ alkyl, C₁₋₈ perfluoroalkyl, C₃₋₆ cycloalkyl,phenyl or benzyl, R₅₈ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, phenylor benzyl, R₅₉ is a group of formula --NR₅₅ R₅₆, --OR₅₆, --NHC(O)NH₂,--NHC(S)NH₂, --NHSO₂ benzyl or --NHSO₂ phenyl (wherein R₅₅ and R₅₆ areas defined above);

Preferably B₅₀ is a group selected from the groups represented by xv toxxii below (wherein in each case Z₅₁ is a bond to X₅₀ and the other freevalency is connected to the --(CH₂)_(r) --Het group); ##STR15## whereinR₁₈₀ is hydrogen, halo, (preferably bromo), fluoro, C₁₋₆ alkyl, C₂₋₆alkenyl, C₁₋₆ fluoroalkyl, C₁₋₆ alkoxy, formyl, carboxy or a group ofthe formula --COR₁₈₃ (wherein R₁₈₃ represents C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkoxy or a group of formula --NR₁₈₄ R₁₈₅, (wherein R₁₈₄ and R₁₈₅are each independently hydrogen or C₁₋₄ alkyl or together form asaturated heterocyclic ring having 5 or 6 ring members and optionallycomprising in the ring one oxygen atom)); R₁₈₁ and R₁₈₂ are eachindependently hydrogen, halo, fluoro, nitro, amino, C₁₋₄ alkylamino,di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄ alkoxy or a groupof the formula --SO₂ NHR₁₉₁ (wherein R₁₉₁ is hydrogen, C₁₋₅ alkyl, arylor arylmethyl); and A₁₂₀ is oxygen, sulphur, or a group of formula--NR₁₈₆ -- {wherein R₁₈₆ is hydrogen or a group selected from C₁₋₆alkyl, C₃₋₆ alkenyl, C₁₋₆ alkoxy, or a group of formula --COR₁₈₇ or--SO₂ R₁₈₈ [wherein R₁₈₇ and R₁₈₈ are each C₁₋₆ alkyl, C₂₋₆ alkenyl,C₁₋₆ alkoxy or a group of formula --NR₁₈₉ R₁₉₀ (wherein R₁₈₉ and R₁₉₀,which may be the same or different, each independently represent ahydrogen atom or a C₁₋₄ alkyl group or together complete a saturatedheterocyclic ring having 5 or 6 ring menders and optionally comprisingin the ring one oxygen atom)]} and wherein preferably the free valencydescribed above is located at the 5 position of the ring; ##STR16##wherein R₂₀₀ and R₂₀₁ are each independently selected from the listprovided to define R₁₈₀ above and R₂₀₂ and R₂₀₃ are each independentlyselected from the list provided to define R₁₈₁ above and whereinpreferably the free valency described above located at the 5 position ofthe ring; ##STR17## wherein R₂₁₀, R₂₁₁ and R₂₁₂ are each independentlyhydrogen, halo, fluoro, nitro, C₁₋₆ alkyl C₁₋₆ acyloxy, C₃₋₆ cycloalkyl,C₁₋₆ alkoxy, hydroxy-C₁₋₄ alkyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl,C₁₋₄ alkylsulphonyl, trifluoromethyl, aryl, furyl or a group of formula--NHSO₂ R₂₁₃, --SO₂ NHR₂₁₃ or --NR₂₁₃ R₂₁₄ wherein R₂₁₃ and R₂₁₄ areeach independently hydrogen, C₁₋₆ alkyl, benzyl or phenyl or, when R₂₁₀and R₂₁₁ are bonded to adjacent carbon atoms, they may together completea fused aromatic ring; and A₁₃₀ is carbonyl, methylene, or a group offormula --CH(CO₂ C₁₋₄ alkyl)--, --CH(CO₂ H)--, --CH(CN)--,--CH(tetrazolyl)-- or --CH(CONHSO₂ R₂₁₅)-- wherein R₂₁₅ is aryl,heteroaryl, C₃₋₇ cycloalkyl or C₁₋₄ alkyl (optionally substituted witharyl, heteroaryl, hydroxy, sulphydryl, C₁₋₄ alkyl, C₁₋₄ alkoxy, C₁₋₄alkylthio, methyl, halo, fluoro, nitro, carboxy,carboxy (C₁₋₄ alkyl),amino, ii (C₁₋₄ alkyl)amino, or a group of formula --PO₃ H or--PO(OH)[O--(C₁₋₄ alkyl)] and wherein preferably the free valencydescribed above is located at the 5 position of the ring; ##STR18##wherein R₂₂₀ and R₂₂₁ are each hydrogen, halo, fluoro, nitro, amino,C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄alkoxy or a group of the formula --SO₂ NHR₂₂₈ (wherein R₂₂₈ is hydrogen,C₁₋₅ alkyl, aryl or arylmethyl); and --A₁₄₀ --A₁₄₁ -- are a group of theformula --N═CR₂₂₂ --, --CR₂₂₂ ═CR₂₂₃ -- --CHR₂₂₂ --CHR₂₂₃ --;

wherein R₂₂₂ and R₂₂₃ are each independently hydrogen, halo fluoro,alkyl, haloalkyl; C₃₋₇ cycloalkyl or arylalkyl (wherein aryl is phenyloptionally substituted with halo, fluoro, alkyl, alkoxy, alkylthio,hydroxy, alkanoyl, nitro, amino, trifluoromethyl, alkylamino ordialkylamino) or a group of formula --COR₂₂₄ (wherein R₂₂₄ is hydrogen,C₁₋₆ alkyl, C₃₋₆ cycloalkyl or a group of formula --OR₂₂₅ or --NR₂₂₆R₂₂₇ wherein R₂₂₅ is hydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl, aryl,arylalkyl or a 5 to 7 membered carbocyclic ring which may have another 5to 7 membered carbocyclic ring fused thereto and R₂₂₆ and R₂₂₂ are eachindependently hydrogen, C₁₋₄ alkyl, phenyl, benzyl, α-methyl benzyl ortogether form a C₃₋₄ cyclic group optionally containing nitrogen and/oroxygen in the ring) and wherein preferably the free valency describedabove is located at the 5 position of the ring; ##STR19## wherein R₂₃₀and R₂₃₁ are each independently hydrogen, halo, fluoro, nitro, amino,C₁₋₄ alkylamino, di(C₁₋₄ alkyl)amino, trifluoromethyl, C₁₋₄ alkyl, C₁₋₄alkoxy or a group of formula --SO₂ NHR₂₃₄ (wherein R₂₃₄ is hydrogen,C₁₋₅ alkyl, aryl or arylmethyl); A₁₅₀ and A₁₅₁ are each independentlyoxygen, sulphur or a group of the formula --NR₂₃₂ -- or --CR₂₃₂ R₂₃₃ --wherein R₂₃₂ and R₂₃₃ are each independently hydrogen, C₁₋₆ alkyl, C₃₋₆cycloalkyl, phenyl or benzyl and wherein preferably the free valencydescribed above is located at the 5 position of the ring; ##STR20##wherein --A₁₆₀ --A₁₆₁ -- is a group of formula ═C(R₂₃₉)--N═ or═N--C(R₂₃₂)═ and wherein R₂₃₀ R₂₃₁ and R₂₃₂ are each independentlyhydrogen, halo, fluoro, nitro, amino, C₁₋₄ alkyl, C₄ alkylamino, di(C₁₋₄alkyl)amino, C₁₋₄ alkoxy, trifluoromethyl, or a group of formula --SO₂NHR₂₃₃ (wherein R₂₃₃ is hydrogen, C₁₋₅ alkyl, aryl or arylmethyl);##STR21## wherein R₂₄₀ to R₂₄₃ are each independently hydrogen, halo,fluoro, C₁₋₆ alkyl, C₁₋₆ perfluoroalkyl, C₁₋₆ alkoxy or C₁₋₆alkoxyalkyl; or ##STR22## wherein --A₁₇₀ ═A₁₇₁ -- is a group of formula--C(R₂₅₀)═N-- or --C(R₂₅₁)═C(R₂₅₂)-- wherein R₂₅₀ is hydrogen or C₁₋₇alkyl and R₂₅₁ and R₂₅₂ are each hydrogen, halo, fluoro, C₁₋₇ alkyl,C₁₋₇ alkoxy, C₂₋₇ alkenyloxy, phenoxy, benzyloxy, trifluoromethyl or agroup of formula --S(O)_(f) --R₂₅₃ (wherein f is 0 or an integer from 1to 2 and R₂₅₃ is hydrogen or C₁₋₇ alkyl).

Preferably, r is 1.

Preferably Het is a group of any of the following formulae, in which ineach case the symbols are as defined in the corresponding patentpublication(s) identified in brackets. Preferred and/or specificheterocycles are as identified in said corresponding patentpublication(s): ##STR23##

Suitably, Her comprises a heterocyclic group, that is a group comprisinga closed organic ring system which ring system contains one or moreoxygen, nitrogen or sulphur atoms. Preferably, Het comprises a stable 5-to 7-membered monocyclic or 7- to 10-membered bicyclic heterocyclic ringwhich is either saturated or unsaturated, and which consists of carbonatoms and up to five, preferably up to three nitrogen, oxygen and/orsulphur atoms (wherein any nitrogen atom may optionally be quaternized),and including any bicyclic group in which any of the above-definedmono-heterocyclic rings is fused to a benzene ring, and wherein the ringis optionally substituted. Such heterocyclic groups include (but are notlimited to): thienyl, furyl, pyranyl, chromenyl, xanthenyl, pyrrolyl,2H-pyrrolyl, imidazolyl, pyrazolyl, pyridyl, pyrazinyl, pyrimidinyl,pyridazinyl, indolizinyl, isoindolyl, 3H-indolyl, indolyl, indazolyl,purinyl, quinolizinyl, quinolyl, phthalazinyl, naphthyridinyl,quinoxalinyl, quinazolinyl, cinnolinyl, pteridinyl, isothiazolyl,isoxazolyl, furazanyl, piperazinyl, pyrrolidinyl, oxazolyl, triazolyland tetrazolyl and any isomers thereof and, where the context permits,dihydro, tetrahydro, mono-one, di-one and tri-one derivatives thereof.Heterocyclic groups of the present invention also include fused ringsbased on any combination of up to three of the foregoing and/or benzeneor naphthalene. Preferred heterocycles are based on benzimidazole andimidazopyridine.

Groups of formula i, ii iii, iv, v, vi, vii, viii, ix, x, xi and xii aredisclosed in a) EP-A-0513533 (Bayer; b) EP-A-0480204 (Fujisawa); c) U.S.Pat. No. 5,124,335 (Merck; d) EP-A-0512676 (Merck); e) EP-A-0512675(Merck; f) WO-A-9112001 (Merck); g) WO-A-9215577 (Searle); h)EP-A-0501269 (Squibb); i) WO-A-9206081 (Warner Lambert); j) U.S. Pat.No. 5,191,086 (Squibb); k) DE-A-4006693 (Schering); and 1) EP-A-0253310(Du Pont) respectively, and preferred groups are as described in thesepublications.

Groups of formula xv, xvi, xvii, xviii, xix, xx, xxi and xxii aredisclosed in m) WO-A-9209600, EP-A-0514193, EP-A-0514192, EP-A-0430709,EP-A-0514198, EP-A-0514197, EP-A-0514216, EP-A-0505954 and EP-A-0514217(Glaxo); n) EP-A-0429257 (Glaxo); o) EP-A-0517357 (Merck); p)EP-A-0488532 (Squibb); q) U.S. Pat. No. 5,190,942 (Squibb); r)EP-A-0508393 (Searle); s) EP-A-0400974 (Merck); and t) EP-A-0528762(Ciba Geigy) respectively, and preferred groups are as described inthese publications.

Preferably Het is a group of any one of the formulae xxv, xxvi, xxvii orxxviii below: ##STR24## wherein R₂₆₀ is hydrogen or C₁₋₄ alkyl and R₂₆₁,R₂₆₂ and R₂₆₃ are each independently hydrogen, C₁₋₄ alkyl, nitro,fluoro, chloro, bromo, cyano, formyl, or a group of the formula --SO_(n)R₂₆₄, --SO₂ NR₂₆₅ R₂₆₆ or --COR₂₆₇ (wherein R₂₆₄, R₂₆₅ and R₂₆₆ are eachindependently hydrogen or C₁₋₄ alkyl, n is 1 or 2 and R₂₆₇ is C₁₋₄ alkylor a group of formula --OR₂₆₈ or --NR₂₆₉ R₂₇₀ wherein R₂₆₈, R₂₆₉ andR₂₇₀ are each independently hydrogen or C₁₋₈ alkyl); ##STR25## whereinR₂₈₀ is hydrogen or C₁₋₆ alkyl; R₂₈₁ is hydrogen, chloro, fluorinated(preferably perfluorinated) C₁₋₂ alkyl (preferably trifluoromethyl orpentafluoroethyl), aryl C₁₋₄ alkyl, C₁₋₄ alkylsulphinyl, C₁₋₄alkylsulphonyl, C₁₋₄ alkylthio, arylsulphinyl, arylsulphonyl, arylthio,arylmethylsulphinyl, arylmethylsulphonyl or arylmethylthio (wherein"aryl" denotes phenyl or 1- or 2-naphthyl each optionally substituted byC₁₋₄ alkyl, C₁₋₄ alkoxy or fluoro, chloro or bromo); and R₂₈₂ ishydroxymethyl, formyl, carboxy, C₂₋₄ alkoxymethyl, C₂₋₄ alkoxycarbonylor carboxymethyl; ##STR26## wherein R₂₉₀ is hydrogen or C₁₋₆ alkyl andeither R₂₉₁ and R₂₉₂ are each independently hydrogen, C₁₋₄ alkyl orphenyl (optionally substituted with C₁₋₄ alkyl, C₁₋₄ alkoxy, fluoro,chloro or bromo) or R₂₉₁ and R₂₉₂ together with the carbon atom to whichthey are attached form a C₃₋₆ spirocycloalkyl ring; or ##STR27## whereinA₁₈₀ is oxygen, sulphur or a group of the formula --NR₃₀₂ -- whereinR₃₀₂ is C₁₋₆ alkyl, A₁₈₁ is nitrogen or methine, R₃₀₀ is hydrogen, C₁₋₄alkyl, C₁₋₄ alkylthio or aryl C₁₋₄ alkyl (wherein "aryl" denotes phenyl,optionally substituted by C₁₋₄ alkyl, C₁₋₄ alkoxy, or fluoro, chloro orbromo) and R₃₀₁ is hydrogen, carboxy, carbamoyl or a group of formula--C(O)NR₃₀₃ R₃₀₄ (wherein R₃₀₃ and R₃₀₄ are each independently C₁₋₄alkyl or hydroxy-substituted C₁₋₄ alkyl or C₁₋₄ alkyl).

Preferably in groups of formula xxv, R₂₆₀ is ethyl, R₂₆₂ is hydrogen andR₂₆₁ and R₂₆₃ are both methyl.

Preferably in groups of formula xxvi, R₂₈₀ is butyl and R₂₈₁ is chloro.

Preferably in groups of formula xxvii, R₂₉₀ is butyl and R₂₉₁ and R₂₉₂together with the carbon atom to which they are attached form aspirocyclopentane ring.

Preferably in groups of formula xxviii, A₁₈₀ is a group of formula--NBu--, R₃₀₀ is hydrogen, and R₃₀₁ is carboxy.

In preferred compounds of formula I, A₅₀ is a group of formula (iii)above, X₅₀ is a bond, B₅₀ is a group of formula (xxi) above and Het is aheterocyclic ring as defined above.

Preferred compounds of formula are compounds of formula II ##STR28##wherein R₃₁₀ is hydrogen or C₁₋₄ alkyl; A₁₉₀ is oxygen, sulphur or agroup of the formula --NR₃₁₉ -- wherein R₃₁₉ is hydrogen or C₁₋₄ alkyl;

R₃₁₁, R₃₁₂, R₃₁₃ and R₃₁₄ are each independently hydrogen, fluoro,chloro, bromo, C₁₋₄ alkyl, C₁₋₄ alkoxy, nitro, cyano, carboxy, C₂₋₄alkoxycarbonyl, C₁₋₄ alkylthio, C₁₋₄ alkylsulphinyl, C₁₋₄alkylsulphonyl, phenyl (optionally substituted by C₁₋₄ alkyl, C₁₋₄alkoxy, fluoro, chloro or bromo), C₁₋₄ alkylsulphonylamino or C₁₋₆alkylaminosulphonyl; R₃₁₅ is hydrogen or C₁₋₄ alkyl; and R₃₁₆, R₃₁₇ andR₃₁₈ are each independently hydrogen, C₁₋₄ alkyl, nitro, fluoro, chloro,bromo, cyano, formyl or a group of the formula --SO_(g) R₃₂₀, --SO₂NR₃₂₁ R₃₂₂ or --COR₃₂₃ (wherein R₃₂₀, R₃₂₁, R₃₂₂ are each independentlyhydrogen or C₁₋₄ alkyl, g is 1 or 2 and R₃₂₃ is C₁₋₄ alkyl or a group ofthe formula --OR₃₂₄ or --NR₃₂₅ R₃₂₆ wherein R₃₂₄, R₃₂₅ and R₃₂₆ are eachindependently hydrogen or C₁₋₄ alkyl);

and pharmaceutically acceptable salts thereof.

Particularly preferred compounds of formula I are represented by formulaIII ##STR29## wherein A₁₉₀, R₃₁₀, R₃₁₅, R₃₁₆, R₃₁₇ and R₃₁₈ are each asdefined above;

and pharmaceutically acceptable salts thereof.

Especially preferred compounds of formula I are represented by formulaIV: ##STR30## in which A₁₉₀ and R₃₁₀ are as defined above; andpharmaceutically acceptable salts thereof.

In preferred compounds of formulae II, III and IV, A₁₉₀ is oxygen andR₃₁₀ is hydrogen.

Further preferred compounds of formula I are represented by formula V##STR31## and pharmaceutically acceptable salts thereof; wherein R₃₃₀ isC₂₋₁₀ alkyl, C₃₋₁₀ alkenyl or a group of formula --(CH₂)_(h) C₃₋₆cycloalkyl, or --(CH₂)_(h) phenyl, wherein h is 0 or an integer from 1to 8 (optionally substituted by up to three of C₁₋₆ alkyl, nitro, cyano,halo, fluoro, C₁₋₃ perfluoroalkyl, C₁₋₃ perfluoroalkylsulphonyl, C₁₋₆alkylsulphonyl, C₁₋₆ alkylthio, hydroxy, C₁₋₆ alkoxy, or a group offormula --NR₃₃₄ R₃₃₅, --CO₂ R₃₃₄, --CONR₃₃₄ R₃₃₅ , --PO(OR₃₃₄)₂, --NR₃₃₄CHO, --NR₃₃₄ O(C₁₋₆ alkyl) or --NR₃₃₄ COR₃₃₆ (wherein R₃₃₄ and R₃₃₅ areeach independently hydrogen or C₁₋₄ alkyl and R₃₃₆ is C₁₋₃perfluoroalkyl);

A₂₀₀ is a bond, sulphur or oxygen; R₃₃₁ is hydrogen, halo, fluoro,formyl, nitro, C₁₋₃ perfluoroalkyl, cyano C₁₋₆ alkyl, phenyl,hydroxymethyl, or a group of formula --CO₂ R₃₃₈, --CONR₃₃₈ R₃₃₉ or--NR₃₃₈ R₃₃₉ (wherein R₃₃₈ and R₂₃₉ are each independently hydrogen orC₁₋₄ alkyl);

m is 0 or an integer from 1 to 4;

B₆₀ is 1,4-phenylene, 1,4-naphthylene, or 2,5-pyridylene, optionallysubstituted with one or more of halo, fluoro, C₁₋₄ alkyl, nitro,hydroxy, C₁₋₄ alkoxy C₁₋₄ alkylsulphonyl, C₁₋₃ perfluoroalkyl, nitrile,or a group of formula --SO₂ NHR₃₈₈, --NHSO₂ R₃₃₈ or --CONR₃₃₈ R₃₃₉(wherein R₃₃₈ and R₃₃₉ are each as defined above;

A₂₀₁ is oxygen, sulphur, or a group of formula --NR₃₃₇ -- (wherein R₃₃₇is hydrogen or C₁₋₄ alkyl);

R₃₃₃ is hydrogen or C₁₋₄ alkyl;

and R₃₃₂ is a group selected from the groups represented by xxx toxxxiii below: ##STR32## wherein R₃₄₀ and R₃₄₁ are each independentlyhydrogen, C₁₋₆ alkyl, C₃₋₆ cycloalkyl or a group of formulaphenyl--Y--₇₀ --, biphenyl--Y₇₀ --, naphthyl--Y₇₀ --, thienyl--Y₇₀ --,furyl--Y₇₀ --, pyridyl --Y₇₀ --, pyrazolyl--Y₇₀ --, imidazolyl--Y₇₀ --,pyrrolyl --Y₇₀ --, triazolyl--Y₇₀ --, oxazolyl--Y₇₀ --, isoxazolyl--Y₇₀--, thiazolyl--Y₇₀ --, or tetrazolyl --Y₇₀ --, with each aryl orheteroaryl group optionally substituted by hydroxy, nitro, C₁₋₃perfluoroalkyl, C₁₋₃ perfluoroalkylsulphonyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, C₁₋₆ alkyl, C₁₋₆ alkoxy, halo, fluoro, or a group offormula --NR₃₄₃ R₃₄₄, --CO₂ R₃₄₃, --SO₂ NHR₃₄₃, --SO₃ H, --CONR₃₄₃ R₃₄₄,--NR₃₄₃ CHO, --NR₃₄₃ CO(C₁₋₃ perfluoroalkyl), or --NR₃₄₃ CO(C₁₋₆ alkyl)wherein R₃₄₃ and R₃₄₄ are each independently hydrogen or C₁₋₆ alkyl ;Y₇₀ is a bond, oxygen, sulphur or C₁₋₆ alkylene optionally substitutedby phenyl or benzyl, (wherein each phenyl or benzyl group is optionallysubstituted by halo, nitro, trifluoromethyl, C₁₋₆ alkyl, C₁₋₆ alkoxy,cyano or a group of formula --CO₂ R₃₄₅ wherein R₃₄₅ is hydrogen or C₁₋₄alkyl); R₃₄₂ is --Y₇₁ --COOR₃₄₆ (wherein R₃₆₆ is hydrogen C₁₋₆ alkyl, or2-di(C₁₋₆ alkyl)-amino-2-oxyethyl); --Y₇₁ CONR₃₄₇ R₃₄₈ (wherein R₃₄₇ andR₃₄₈ are each independently hydrogen or C₁₋₆ alkyl), or --Y₇₁-tetrazol-5-yl (wherein Y₇₁ is a bond, vinylene, methyleneoxymethylene,methylene (each optionally substituted by C₁₋₆ alkyl, one or two benzylgroups, thienylmethyl, furylmethyl) or a group of formula --C(O)NHCHR₃₄₉--, (wherein R₃₄₉ is hydrogen, C₁₋₆ alkyl, phenyl, benzyl,thienylmethyl, or furylmethyl)); ##STR33## wherein R₃₅₀ and R₃₅₁ areeach independently hydrogen or C₁₋₆ alkyl; R₃₅₂ is hydrogen, C₁₋₈ alkyl,or a group of formula thienyl--Y₈₀ --, furyl--₈₀ --, pyrazolyl--Y₈₀ --,imidazolyl--Y₈₀ --, thiazolyl--Y₈₀ --, pyridyl--Y₈₀ --, tetrazolyl--Y₈₀--, pyrrolyl--Y₈₀ --, triazolyl--Y₈₀ --, oxazolyl--Y₈₀ --,isoxazolyl--Y₈₀ -- or phenyl--Y₈₀ -- (wherein Y₈₀ is a bond or C₁₋₆alkylene) with each aryl or heteroaryl group optionally substituted byC₁₋₆ alkyl, C₁₋₆ alkoxy, C₁₋₄ perfluoroalkyl, C₁₋₆ alkylthio, C₁₋₆alkylsulphonyl, C₁₋₄ perfluoroalkylsulphonyl, halo, hydroxy, nitro or agroup of formula --NR₃₅₄ R₃₅₅, --CO₂ R₃₅₄, --SO₂ NHR₃₅₄, --SO₃ H,--CONR₃₅₄ R₃₅₅, --NR₃₅₄ CHO, --NR₃₅₄ COR₃₅₆, or --NR₃₅₄ COC₁₋₆ alkyl(wherein R₃₅₄ and R₃₅₅ are each independently hydrogen or C₁₋₄ alkyl andR₃₅₆ is C₁₋₄ perfluoroalkyl); R₃₅₃ is a group of formula --CO₂ R₃₅₈,--CONR₃₅₈ R₃₅₇, or tetrazol-5-yl (wherein R₃₅₇ and R₃₅₈ are eachhydrogen or C₁₋₆ alkyl); and

n is 0 or an integer from 1 to 5; ##STR34## wherein R₃₆₀ is hydrogen,C₁₋₆ alkyl, C₃₋₆ alkenyl, C₁₋₅ alkylcarbonyl, or a group of formula--(CH₂)₀₋₃ phenyl; R₃₆₁ is hydrogen, C₁₋₆ alkyl, C₃₋₆ alkenyl, or--(CH₂)₀₋₃ phenyl; R₃₆₂ is a group of formula --CO₂ R₃₆₄, --CONR₃₆₄R₃₆₅, (wherein R₃₆₄ and R₃₆₅ are each independently hydrogen or C₁₋₆alkyl) or tetrazol-5-yl;

n and p are each independently 0 or an integer from 1 to 4; and

R₃₆₃ is phenyl, naphthyl, thienyl, furyl, pyridyl, pyrimidyl,imidazolyl, thiazolyl, triazolyl, tetrazolyl, pyrazolyl, pyrrolyl,oxazolyl, or isoxazolyl, with each aryl or heteroaryl group optionallysubstituted by C₁₋₆ alkyl, C₁₋₆ alkoxy, halo, fluoro, hydroxy, nitro,C₁₋₄ perfluoroalkyl, C₁₋₆ alkylsulphonyl, C₁₋₄ perfluoroalkylsulphonyl,C₁₋₆ alkylthio, or a group of formula --NR₃₆₆ R₃₆₇, --CO₂ R₃₆₆,--CONR₃₆₆ R₃₆₇, --SO₃ H, --SO₂ NHR₃₆₆, --NR₃₆₆ CHO; --NR₃₆₆ CO(C₁₋₄perfluoroalkyl or --NRCOC₁₋₆ alkyl (wherein R₃₆₆ and R₃₆₇ are eachindependently hydrogen or C₁₋₆ alkyl); ##STR35## wherein R₃₇₀ is a groupof formula --CO₂ R₃₇₃, CONR₃₇₃ R₃₇₄, or tetrazol-5-yl; A₂₁₀ is a bond ora carbonyl group; R₃₇₁ is hydrogen, C₁₋₈ alkyl, C₃₋₆ cycloalkyl, phenyl,phenyl C₁₋₄ alkylene or biphenyl or biphenyl C₁₋₃ alkylene wherein eachphenyl group is optionally substituted by to three substituents selectedfrom C₁₋₆ alkyl, nitro, halo, fluoro, hydroxy, C₁₋₆ alkyl, or a group offormula --NR₃₇₅ R₃₇₆, --CO₂ R₃₇₆, or --CONR₃₇₅ R₃₇₆ (wherein R₃₇₅ andR₃₇₆ are each independently hydrogen or C₁₋₄ alkyl); R₃₇₂ is hydrogen orC₁₋₆ alkyl ; R₃₇₃ and R₃₇₄ are independently hydrogen, C₁₋₄ alkyl, or agroup of the formula --(CH₂)₀₋₄ phenyl; and n is 0 or an integer from 1to 4.

In preferred compounds of formula V, B₆₀ is 1,4-phenylene, optionallysubstituted as in the definition above.

Preferred compounds of formula V are represented by formula VI:##STR36## wherein R₃₃₀, A₂₀₀, R₃₃₁, R₃₃₂, A₂₀₁ and R₃₃₃ are each asdefined above, and R₄₀₀ and R₄₀₁ are each independently hydrogen, halo,fluoro, C₁₋₄ alkyl, nitro, hydroxy, C₁₋₄ alkoxy, C₁₋₄ alkylsulphonyl,C₁₋₃ perfluoroalkyl, nitrilo or a group of formula --SO₂ NHR₄₀₂, --NHSO₂R₄₀₂ or --CONR₄₀₂ R₄₀₃ (wherein R₄₀₂ and R₄₀₃ are each hydrogen or C₁₋₄alkyl); and the other substituents are each as defined above.

Where not otherwise indicated, the terms "alkyl", "alkenyl", and"alkynyl" as used above denote straight or branched radicals having from1 to 10 carbon atoms, preferably 1 to 6 carbon atoms and more preferablyfrom 1 to 4 carbon atoms.

Where not otherwise indicated, the term "aryl" as used above denotesphenyl or naphthyl, optionally substituted with halo, fluoro, C₁₋₄alkyl, C₁₋₄ alkoxy, nitro, trifluoromethyl, C₁₋₄ alkylthio, hydroxy,amino, di(C₁₋₄ alkyl)amino, carboxy or carboxy esterified with C₁₋₄alkyl.

Where not otherwise indicated, the term "heteroaryl" as used abovedenotes a five or six membered aromatic ring containing up to 3 ofoxygen, nitrogen and/or sulphur and optionally substituted by hydroxy,sulphydryl, C₁₋₄ alkyl, C₁₋₄ alkoxy, trifluoromethyl, halo, fluoro,nitro, carboxy, carboxy esterified with C₁₋₄ alkyl, amino, C₁₋₄alkylamino or di(C₁₋₄ alkyl)amino.

It will be understood that a group containing a chain of 3 or morecarbon atoms may be straight or branched, for example, propyl includesn-propyl and isopropyl and butyl includes n-butyl, sec-butyl, isobutyland tert-butyl. The term "halo" as used herein signifies bromo, chloroor iodo.

Specific compounds of the present invention are:

3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione;

3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione;

3-amino-4-[4'-(2-ethyl-5,7-dimethyl -3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione;

3-[4'-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-3,1]-4-isopropoxycyclobut-3-ene-1,2-dione;

3-[4'-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione;

2-ethyl-3-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-5,7,N,N-tetramethyl-3H-imidazo[4,5-b]pyridine-6-sulphonamide;

2-ethyl-3-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-5,7,N,N-tetramethyl-3H-imidazo-[4,5-b]pyridine-6-sulphonamide;

3-[4'-(6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]-pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione;

2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethyl pivalate;

4-ethyl-1-[2'-(3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde;

4-ethyl-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde;

3-dimethylamino-4-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione;

1-[2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxy]ethylpivalate;

ethyl4-[N-butyl-N-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]amino]pyrimidine-5-carboxylate;

ethyl4-[N-butyl-N-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethylamino]pyrimidine-5-carboxylate;

4-[N-butyl-N-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)-biphenyl-4-ylmethylamino]pyrimidine-5-carboxylicacid;

3-[4'-(2-butyl-5-oxo-2-imidazoline-4-spirocyclopent-1-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione;

3-[4'-(2-butyl-5-oxo-2-imidazoline-4-spirocyclopent-1-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione;

2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl)]-1H-imidazole-5-carboxaldehyde;

2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxaldehyde;

3-[4'-(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione;

methyl2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate;

methyl2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl)-1H-imidazole-5-carboxylate;

2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylic acid; and

(E)-2-benzyl-3-[2-butyl-4-chloro-1-[4(2-hydroxy-3,4-dioxocyclobut-1-en-1-ylbenzyl]-1H-imidazol-5-yl]propenoicacid;

and, where appropriate, pharmaceutically acceptable salts and/orsolvates thereof, such as alkali metal salts, preferably sodium salts,and hydrochlorides.

The present invention also provides compounds of formula I to Vi whereinA₅₁, A₁₉₀ and A₂₀₁ are each oxygen modified in that R₅₀, R₃₁₀ and R₃₃₃are each a group capable of being hydrolysed in vivo to leave compoundsof formula I to VI wherein R₅₀, R₃₁₀ and R₃₃₃ are hydrogen, such groupsincluding groups of formula xxxv ##STR37## wherein R₄₁₀ is hydrogen orC₁₋₄ alkyl and R₄₁₁ C₁₋₄ alkyl or C₃₋₆ cycloalkyl; those of formulaxxxvi ##STR38## wherein R₄₁₂ and R₄₁₃ are each independently hydrogen orC₁₋₄ alkyl; and those of formula xxxvii ##STR39## wherein R₄₁₄ ishydrogen or C₁₋₄ alkyl.

Compounds bearing such groups are commonly described as `pro-drugs`. Itwill be appreciated by a person skilled in the art that a wide varietyof other groups which are removable in vivo may be used in such`pro-drugs`. Examples of such groups and methods for their addition canbe found in an article by H. Bundgaard, (Drugs of the Future (1991), 16,443) and in the books "Design of Prodrugs" (Editor H Bundgaard, 1985Elsevier Science Publishers BV, Biomedical Division) and "Pro-drugs asNovel Drug Delivery Systems" (Editors T. Higuchi and V. Stella, 1975,ACS Symposium Series 14, American Chemical Society, Washington, D.C.).Unless otherwise stated, all references below to `compounds of formula Ito VI` include, where appropriate, such `pro-drugs` of compounds offormula I to VI.

Compounds of formula I to VI may form salts with acids or bases.Reference hereinafter to compounds of formula I to VI includes all suchsalts of compounds of formula I to VI which are pharmaceuticallyacceptable. Particularly suitable salts of compounds of formula I to VIinclude, for example, alkali metal salts (such as sodium and potassiumsalts), alkaline earth metal salts (such as magnesium and calciumsalts), aluminum and ammonium salts, salts with suitable organic basessuch as alkylamines, N-methyl-D-glucamine and salts with amino acidssuch as arginine and lysine. Also suitable are salts with inorganicacids, for example hydrochlorides, hydrobromides, sulphates andphosphates, and salts with organic acids, for example maleates andfumarates.

It will be appreciated by those skilled in the art that certaincompounds of formula I to VI or their salts contain one or more chiralcentres. When a compound of formula I to VI contains a single chiralcentre it may exist in two enantiomeric forms which may be obtainedseparately by methods known to those skilled in the art. Such methodstypically include resolution via formation of diastereoisomeric salts orcomplexes which may be separated, for example, by crystallisation;formation of diastereoisomeric derivatives which may be separated, forexample, by crystallization, gas-liquid or liquid chromatography;selective derivatisation of one enantiomer by reaction with anenantiomer-specific reagent, for example enzymatic oxidation orreduction; or gas-liquid or liquid chromatography in a chiralenvironment, for example on a chiral support or in the presence of achiral solvent. Alternatively, specific enantiomers may be synthesisedby asymmetric synthesis using optically active reagents, substrates,catalysts or solvents, or converting one enantiomer into the other byasymmetric transformation. The present invention includes eachenantiomer of compounds of formula I to VI and mixtures thereof. When acompound of formula I to VI contains more than one chiral centre it mayexist in diastereoisomeric forms. The diastereoisomers may be separatedby methods known to those skilled in the art, for example chromatographyor crystallisation. The present invention includes each diastereoisomerof compounds of formula I to VI and mixtures thereof. It will beappreciated that where the active moiety is transformed by theseparation procedures described above, a further step is required toconvert the product to the active moiety.

Certain compounds of formula I to VI or their salts may exist in morethan one crystal form and the present invention includes each crystalform and mixtures thereof.

Certain compounds of formula I to VI may exist in zwitterionic form andthe present invention includes each zwitterionic form and mixturesthereof.

Certain compounds of formula I to Vl or their salts may also exist inthe form of solvates, for example hydrates, and the present inventionincludes each solvate and mixtures thereof.

The present invention also provides pharmaceutical compositions whichcomprise a compound of formula I to VI or salts thereof together with apharmaceutically acceptable diluent or carrier. Specific compounds whichmay be incorporated into the compositions of this invention are thenovel compounds disclosed above.

As used hereinafter, the term "active compound" denotes a compound offormula I to VI, preferably formula II. In therapeutic use the activecompound may be administered orally, rectally parenterally or topically,preferably orally Thus the therapeutic compositions of the presentinvention may take the form of any of the known pharmaceuticalcompositions for oral, rectal, parenteral or topical administration. Thecompositions may be formulated in a manner known to those skilled in theart so as to give a controlled release of the compounds of the presentinvention. Pharmaceutically acceptable carriers suitable for use in suchcompositions are well known in the art of pharmacy. The compositions ofthe invention suitably contain 0.1-90% by weight of active compound. Thecompositions of the invention are generally prepared in unit dosageform.

Compositions for oral administration are the preferred compositions ofthe invention and these are the known pharmaceutical forms for suchadministration, for example tablets, capsules, syrups and aqueous oroily suspensions. The excipients used in the preparation of thesecompositions are the excipients known in the pharmacists' art.

Tablets may be prepared by mixing the active compound with an inertdiluent, such as lactose or calcium phosphate, in the presence ofdisintegrating agents, for example maize starch, and lubricating agents,for example magnesium stearate, and tableting the mixture by knownmethods. Such tablets may if desired be provided with enteric coatingsby known methods, for example by the use of cellulose acetate phthalate.Similarly capsules, for example hard or soft gelatin capsules containingthe active compound with or without added excipients, may be prepared byconventional means and, if desired, provided with enteric coatings in aknown manner. Enteric coated compositions of the invention may beadvantageous, depending on she nature of the active compound. Thetablets and capsules may conveniently each contain 1-500 mg of theactive compound. Other compositions for oral administration include, forexample, aqueous suspensions containing the compound of formula I to VIin an aqueous medium in the presence of a non-toxic suspending agentsuch as sodium carboxymethylcellulose, and oily suspensions containing acompound of the present invention in a suitable vegetable oil, forexample arachis oil.

Compositions of the invention suitable for rectal administration are theknown pharmaceutical forms for such administration, for examplesuppositories with semi-synthetic glycerides or polyethylene glycolbases.

Compositions of the invention suitable for parenteral administration arethe known pharmaceutical forms for such administration, for examplesterile suspensions in aqueous and oily media or sterile solutions in asuitable solvent.

Compositions for topical administration may comprise a matrix in whichthe active compound is dispersed so that it is held in contact with theskin in order to administer the compound of formula I to VItransdermally. Alternatively the active compound may be dispersed in acream or ointment base.

In some formulations it may be beneficial to use the compounds of thepresent invention in the form of particles of very small size, forexample as obtained by fluid energy milling.

In the compositions of the present invention the active compound may, ifdesired, be associated with other compatible pharmacologically activeingredients, for example a β-adrenoceptor antagonist such as atenolol,propranolol, oxprenolol, nadolol or timolol, and/or a diuretic such asbendrofluazide, ethacrynic acid or frusemide, and/or an angiotensinconverting enzyme inhibitor such as captopril or enalapril, and/orvasodilators such as hydralazine hydrochloride, flosequinan, sodiumninroprusside, glyceryl trinitrate or molsidomine, and/or potassiumchannel activators such as lemakalim or pinacidil, and/or anα-adrenoceptor antagonist such as prazosin or labetalol, and/or otherhypotensives such as clonidine, diazoxide, α-methyldopa or ketanserin,and/or positive inotropes such as milrinone, digitalis or dobutamine,and/or PDE inhibitors such as zaprinast, and/or specific bradycardicagents such as alinidine or falipamil, an endothelin antagonist and/oran endothelin converting enzyme inhibitor, and/or a renin inhibitor,and/or a thrombolytic agent such as streptokinase.

The therapeutic activity of compounds of formula I to VI has beendemonstrated by means of tests on standard laboratory animals. Suchtests include, for example, the oral administration of the compounds toa strain of spontaneously hypertensive rat. Thus, compounds of formula Ito VI are useful for reducing blood pressure in hypertensive mammals.Whilst the precise amount of active compound administered will depend ona number of factors, for example the age of the patient, the severity ofthe condition and the past medical history and always lies within thesound discretion of the administering physician, a suitable dose forenteral administration to mammals, including humans, is generally withinthe range 0.01-25 mg/kg/day, more usually 0.2-10 mg/kg/day given insingle or divided doses. For parenteral administration, a suitable doseis generally within the range 0.001-2.5 mg/kg/day, more usually 0.005-1mg/kg/day given in single or divided doses or by continuous infusion.Oral administration is preferred.

Compounds of formula I to VI and salts thereof are angiotensin IIantagonists and therefore are useful in the treatment of hypertension inmammals, including humans. Compounds of formula I to VI are alsoindicated as suitable for use in the treatment of acute and chroniccongestive heart failure, glaucoma, primary and secondaryhyperaldosteronism, primary and secondary pulmonary hypertension corpulmonale, renal failure, renal vascular hypertension, angina, migraine,left ventricular dysfunction, peripheral vascular disease (eg Raynaud'sdisease), scleroderma, diabetic nephropathy, and prevention of coronaryinsufficiency after myocardial infarction.

Accordingly, the present invention further provides a method fortreatment of the said conditions, the use of any compound of formula Ito VI in the treatment of the said conditions and the use of anycompound of formula I to VI in the manufacture of a medicament for thetreatment of the said conditions.

Processes for the preparation of compounds of formula I will now bedescribed. These processes form a further aspect of the presentinvention.

Compounds of formula I wherein R₅₀ is C₁₋₄ alkyl, A₅₁ is oxygen and r is1 may be prepared by reacting a compound of formula X ##STR40## whereinL is a leaving group such as halo (e.g. bromo); and R₅₀ is C₁₋₄ alkyl;with a corresponding compound of formula Het-H, wherein Het is asdefined in the lists of structural formulae above; in a solvent inert tothe conditions of the reaction; preferably in the presence of a base.

Compounds of formula Het-H may be prepared by methods described in thecorresponding patent publications identified above. In particular,compounds of formula Het-H wherein Het is a group of formula xxv, xxviiand xxviii may be prepared as described in EP-A-0400974 (Merck),WO-A-9114679 (Sanofi) and EP-A-0475206 (Abbott) respectively.

Compounds of formula Het-H wherein Het is a group of formula xxvi, maybe prepared by methods described in Schunack [Arch. Pharmaz. (1974) Vol.307, p46] (for compounds wherein R₈ is hydrogen), EP-A-0253310 (forcompounds wherein R₈ is chloro or trifluoromethyl), EP-A-0324337 (forcompounds wherein R₈ is pentafluoroethyl), WO-A-9200977 (for compoundswherein R₈ is C₁₋₄ alkyl) and EP-A-0465368 (for compounds wherein R₈ isC₁₋₄ alkylsulphinyl, C₁₋₄ alkylsulphonyl, C₁₋₄ alkylthio, arylsulphinyl,arylsulphonyl, arylthio, arylmethylsulphinyl, arylmethylsulphonyl orarylmethylthio [wherein "aryl" denotes phenyl optionally substituted byC₁₋₄ alkyl, C₁₋₄ alkoxy or fluoro, chloro or bromo]).

Compounds of formula X wherein L is halo, for example chloro or bromo,may be prepared by reaction of a compound of formula XI ##STR41## with achlorinating agent, for example benzyltriethylammoniumtetrachloroiodate, or a brominating agent, for exampleN-bromosuccinimide; in a solvent inert to the conditions of thereaction.

Compounds of formula XI wherein X₅₀ is a bond such that A₅₀ and B₅₀ aredirectly bonded via a carbon-carbon bond (i.e. when A₅₀ is a group offormula ii, iii, iv or v above and B₅₀ is a group of formula xv, xix,xx, xxi or xxii) may be prepared by reacting a compound of formula XII##STR42## wherein Hal is halo, suitably bromo or iodo; with a compoundof formula XIII

    CH.sub.3 --B.sub.50 --Q.sub.50                             XIII

wherein B₅₀ is a group of formula xv, xix, xx, xxi or xxii above; andQ₅₀ represents a group known for the coupling of aromatic species suchas a boronic acid group of formula --B(OH)₂ or a boronic acid derivativeof formula --B(OAlk)₂ (wherein Alk represents a C₁₋₄ alkyl group) or atrialkyl stannyl group of formula --Sn(Alk)₃ (wherein Alk represents aC₁₋₄ alkyl group); in a solvent inert to the conditions of the reaction;preferably by reaction in the presence of a base, such as sodiumcarbonate; suitably in the presence of a metal catalyst, such as apalladium(0) or nickel(0) catalyst, or by reacting in the same waycompounds of formula XII and XIII modified in that substituents Q₅₀ andHal therein are interchanged.

Compounds of formula XIlI wherein B₅₀ is a group of formula xv, xix, xx,xxi or xxii above are either known from the patent publicationsidentified by the letters (m) and (q) to (t) above or are readilyderivable from compounds described therein by methods well-known in theart (for example by a boronation reaction in which a compound of formulaXIII modified in that Q₅₀ is lithium or a group of formula MgHal(wherein Hal is halo) is reacted with a trialkyl borate (such astriisopropyl borate at from -100° C. to 0° C.) in a solvent (such astetrahydrofuran) inert to the conditions of the reaction. Hydrolysis inthe presence of an acid such as hydrochloric acid may if desired becarried out to produce a substituent of formula --B(OH)₂ on the compoundof formula XIll).

Compounds of formula XII may be prepared by reacting a compound offormula XlV ##STR43## wherein T is a trialkylstannyl group of formula--Sn(Alk)₃ wherein Alk represents a C₁₋₄ alkyl group (suitably a butylgroup); with a compound of formula XV

    Hal--A.sub.50 --I                                          XV

wherein Hal is bromo or iodo, suitably bromo; in a solvent inert to theconditions of the reaction, suitably in the presence of a metalcatalyst, such as a palladium(0) or nickel(0) catalyst.

Compounds of formula XIV may be prepared as described by Liebeskind andFengl in Journal of Organic Chemistry (1990) Vol. 55 pp 5359/5364.

Compounds of formula XV are either known from the patent publicationsidentified by the letters (b) to (e) above, or are readily preparablefrom compounds described therein, for example by appropriate use ofhalogenation reactions as described above.

Compounds of formula XI may also be prepared by reacting a compound offormula XVI

    CH.sub.3 --B.sub.50 --X.sub.50 --A.sub.50 --Met            XVI

wherein Met is lithium or a group of formula MgX wherein X is chloro,bromo or iodo; with a compound of formula XVII ##STR44## wherein Alk isC₁₋₄ alkyl; followed by treatment with an acylating agent, for example,with trifluoroacetic anhydride; in a solvent inert to the conditions ofthe reaction.

Compounds of formula XVII are available commercially from AldrichChemical Co. (UK).

Compounds of formula XVI may be prepared by reacting a compound offormula XVIlI

    CH.sub.3 --B.sub.50 --X.sub.50 --A.sub.50 --Hal            XVIII

wherein Hal is halo, preferably bromo; with a C₁₋₄ alkyl lithiumcompound or magnesium metal; in a solvent inert to the conditions of thereaction.

Compounds of formula XVIl I wherein X₅₀ is a bond such that A₅₀ and B₅₀are bonded via a carbon-carbon bond (i.e. when A₅₀ is a group of formulaii, iii, iv or v above and B₅₀ is a group of formula xv, xix, xx, xxi orxxii) may be prepared by reacting a compound of formula XIII above witha compound of formula XIX

    Hal--A.sub.50 --I                                          XIX

wherein Hal is halo or iodo and A₅₀ is a group of formula ii, iii, iv orv above; in a solvent inert to the conditions of the reaction;preferably by reaction in the presence of a base such as sodiumcarbonate; suitably in the presence of a metal catalyst, such as apalladium(0) or nickel(0) catalyst; or by reacting in the same waycompounds of formula XIII and XIX modified in that the substituents Q₅₀and Hal therein are interchanged.

Compounds of formula XVIII wherein X₅₀ is a bond such that A₅₀ and B₅₀are bonded via a carbon-carbon bond (i.e. when A₅₀ is a group of formulaii, iii, iv or v above and B₅₀ is a group of formula xv, xix, xx, xxi orxxii) may also be prepared by reacting a compound of formula XIII inwhich Q₅₀ is a group of formula --MgHal (wherein Hal is bromo or chloro)with a compound of formula XX

    Hal--A.sub.50 --Hal                                        XX

wherein A₅₀ is a group of formula ii, iii, iv or v above and each Hal isindependently chloro, bromo or iodo; in a solvent inert to theconditions of the reaction; preferably by reaction in the presence of abase, such as sodium carbonate; suitably in the presence of a metalcatalyst, such as a palladium(0) or nickel(0) catalyst, or by reactingin the same way compounds of formula XIII and XX modified in that thesubstituents Q₅₀ and Hal therein are interchanged.

Compounds of formula XIX and XX are either known from the patentpublications identified by the letters (b) to (e) above, or are readilypreparable from compounds described therein.

Compounds of formula I wherein A₅₁ is oxygen, r is 1 and R₅₀ is C₁₋₄alkyl may also be prepared by reacting a compound of formula XXI

    Het--CH.sub.2 --B.sub.50 --X.sub.50 --A.sub.50 --I         XXI

with a compound of formula XlV above; in a solvent inert to theconditions of the reaction; suitably in the presence of a metalcatalyst; for example a palladium (0) or nickel(0) catalyst.

Compounds of formula XXI may be prepared by reacting a compound offormula XXII

    LCH.sub.2 --B.sub.50 --X.sub.50 --A.sub.50 --I             XXII

wherein L is a leaving group, suitably halo, (e.g. bromo or chloro) witha compound of the formula Het-H as described above; in a solvent inertto the conditions of the reaction; preferably in the presence of a base.

Compounds of formula XXI may also be prepared by reacting a compound offormula XXII (or a corresponding compound wherein L is amino) with aprecursor of the corresponding group of formula Het, and then generatingthe Het moiety in situ. Suitable methods are described in the patentpublications identified above.

Compounds of formula XXII wherein L is bromo or chloro may be preparedby reacting a compound of formula XXIII

    CH.sub.3 --B.sub.50 --X.sub.50 --A.sub.50 --I              XXIII

with a chlorinating agent, for example benzyltriethylammoniumtetrachloroiodate, or a brominating agent, for example,N-bromosuccinimide; in a solvent inert to the conditions of thereaction.

Compounds of formula XXIII above wherein X is a bond such that A₅₀ andB₅₀ are bonded via a carbon-carbon bond (i.e. when A₅₀ is a group offormula ii, iii, iv or v above and B₅₀ is a group of formula xv, xix,xx, xxi or xxii) may be prepared by reacting a compound of formula XIII-above with a compound of formula XIX above; in a solvent inert to theconditions of the reaction; preferably by reaction in the presence of abase such as sodium carbonate; suitably in the presence of a metalcatalyst, such as a palladium(0) or nickel(0) catalyst, or by reactingin the same way compounds of formula XIII and XIX modified in that thesubstituents Q₅₀ and Hal therein are interchanged.

It will be appreciated that where a compound of formula Het-H or a groupof formula Het contains a reactive substituent, such as carboxy, it maybe necessary to protect this substituent (for example by esterificationin the case of carboxy) before some of the reactions described above arecarried out. After such reaction, the substituent may be deprotected(for example by acid or alkaline hydrolysis) to provide the freesubstituent as required.

Compounds of formula I wherein A₅₀ is a group of formula vii above, R₅₀is C₁₋₄ alkyl, X₅₀ is a bond, r is 1 and A₅₁ is oxygen may be preparedby reaction of a compound of formula XL ##STR45## wherein L is a leavinggroup such as halo, (e.g. bromo); and R₅₀ is C₁₋₄ alkyl; with acorresponding compound of formula Het-H, wherein Het is as defined inthe lists of structural formulae above; in a solvent (such asdimethylformamide) inert to the conditions of the reaction; preferablyin the presence of a base, such as sodium hydride.

Compounds of formula XL wherein R₅₀ is C₁₋₄ alkyl and L is halo, forexample chloro or bromo, may be prepared by reaction of a compound offormula XLI ##STR46## with a chlorinating agent, for examplebenzyltriethylammonium tetrachloroiodate, or a brominating agent, forexample N-bromosuccinimide; in a solvent inert to the conditions of thereaction.

Compounds of formula XLI may be prepared by reacting a compound offormula XLII ##STR47## with a compound of formula XVII above followed byan acylating agent, for example trifluoroacetic anhydride; in a solventinert to the conditions of the reaction.

Compounds of formula XLII may be prepared by reacting a compound offormula XLIII ##STR48## with a C₁₋₄ alkyllithium reagent, (such asbutyllithium); in a solvent inert to the conditions of the reaction.

Compounds of formula XLIII are known from WO-A-9215577 (Searle).

Compounds of formula I wherein X₅₀ is not a bond but is a spacer groupas defined above may be prepared by reactions as above, modified by useof appropriate alternative aromatic or aliphatic coupling reactions asidentified in FR-A-2669928 (Labs UPSA), EP-A-0323841 (Du Pont),EP-A-0475206 (Abbott), EP-A-0449699 (Labs UPSA), U.S. Pat. No. 5091390(Du Pont), US-A-4880804 Du Pont) and U.S. Pat. No. 5043349 (Du Pont) andthe references therein.

Compounds of formula V wherein A₂₀₁ is oxygen and R₃₃₃ is C₁₋₄ alkyl maybe prepared by reacting a compound of formula L ##STR49## with acompound of formula XIV above (wherein R₅₀ is R₃₃₃); in a solvent inertto the conditions of the reaction; suitably in the presence of a metalcatalyst such as a palladium(0) or nickel 0) catalyst.

Compounds of formula L wherein R₃₃₂ is a group of formula xxx may beprepared by dehydrating a compound of formula LI ##STR50## for exampleby reaction with an acylating agent such as acetic anhydride, followedby a base, such as diazobicyclo[5.4.0]undec-7-ene; in a solvent inert tothe conditions of the reaction.

Compounds of formula LI may be prepared by reacting a compound offormula LII ##STR51## with a compound of formula R₃₄₁ CH₂ R₃₄₂ ; in asolvent inert to the conditions of the reaction; in the presence of abase, such as lithium diisopropylamide. Compounds of formula R₃₄₁ CH₂R₃₄₂ are well-known in the art (e.g. from EP-A-0425211; SmithklineBeecham).

Compounds of formula LII may be prepared by reacting a compound offormula LIII ##STR52## with a compound of formula LIV

    L(CH.sub.2).sub.m --B.sub.60 --Hal                         LIV

wherein Hal is bromo or iodo and L is a leaving group such as bromo orchloro; in a solvent inert to the conditions of the reaction; suitablyin the presence of a base, such as potassium carbonate. This reactionmay give rise to a mixture of isomeric products which may be separatedby conventional means, for example by flash column chromatography.

Compounds of formula LIII are known from EP-A-0425211 (SmithklineBeecham) or are readily derivable from compounds described therein bymethods well-known in the art.

Compounds of formula LIV are well-known in the art.

Compounds of formula L wherein R₃₃₂ is a group of formula xxxi may beprepared by reacting a compound of formula LV ##STR53## wherein Hal isbromo or iodo with a compound of formula LVI ##STR54## in a solventinert to the conditions of the reaction; suitably in the presence of acatalyst, such as N-hydroxysuccinimide.

Compounds of formula LV may be prepared as described in EP-A-0437103(Smithkline Beecham).

Compounds of formula LVI may be prepared as described in EP-A-0437103(Smithkline Beecham).

Compounds of formula L wherein R₃₃₂ is a group of formula xxxii may beprepared by reacting a compound of formula LVII ##STR55## wherein Hal isbromo or chloro and L is a leaving group such as chloro; with a compoundof formula LVIII ##STR56## in a solvent (such as dimethylformamide)inert to the conditions of the reaction; suitably in the presence of abase, such as triethylamine.

Compounds of formula LVIII may be prepared as described in EP-A-0427463(Smithkline Beecham).

Compounds of formula LVII wherein n is greater than 1, are known fromU.S. Pat. No. 4340598 (Takeda) or are readily derivable from compoundsdescribed therein by methods well-known in the art.

Compounds of formula LVII wherein L is halo and n is 1 may be preparedby reacting a compound of formula LIX ##STR57## wherein Hal is bromo orchloro; with a halogenating agent, such as thionyl chloride; in asolvent inert to the conditions of the reaction.

Compounds of formula LlX may be prepared by reacting a compound offormula LX ##STR58## with a reducing agent, such as sodium borohydride;in a solvent inert to the conditions of the reaction.

Compounds of formula LX may be prepared as described in EP-A-0427463(Smithkline Beecham).

Compounds of formula L wherein R₃₃₂ is a group of formula xxxiii whereinR₃₇₀ is carboxyl, A₂₁₀ is carbonyl and R₃₇₂ is C₁₋₆ alkyl may beprepared by hydrolysing a compound of formula LXI ##STR59## wherein R₃₇₂is C₁₋₆ alkyl and R₃₇₃ is as defined above but is not hydrogen; forexample with a base, such as aqueous sodium carbonate solution; in asolvent inert to the conditions of the reaction.

Compounds of formula LXI wherein R₃₇₂ is C₁₋₆ alkyl may be prepared byreacting a corresponding compound wherein R₃₇₂ is hydrogen, with a base,such as sodium hydride, followed by a C₁₋₆ alkyl halide; in a solventinert to the conditions of reaction.

Compounds of formula LXI wherein R₃₇₂ is hydrogen may be prepared byreacting a compound of formula LVII above wherein L is chloro with acompound of formula LXII ##STR60## wherein R₃₇₃ is as defined above butis not hydrogen; in a solvent (such as dimethylformamide) inert to theconditions of the reaction.

Compounds of formula LXII may be prepared as described in WO-A-9200068(Smithkline Beecham).

Compounds of formula L wherein R₃₃₂ is a group of formula xxxiii whereinR₃₇₀ is a group of formula --CO₂ R₃₇₃, A₂₁₀ is a bond and R₃₇₁ and R₃₇₂are both hydrogen may be prepared by hydrolysing a compound of formulaLXIII ##STR61## wherein R₃₇₃ is as defined above but is not hydrogen forexample by hydrolysis with dilute aqueous acid, such as hydrochloricacid; in a solvent inert to the conditions of the reaction.

Compounds of formula LXIII may be prepared by reacting a compound offormula LVII wherein L is chloro with a compound of formula LXIV##STR62## wherein R₃₇₃ is as defined above except hydrogen; in a solvent(such as tetrahydrofuran) inert to the conditions of the reaction.

Compounds of formula LXIV may be prepared as described in WO-A-9200068(Smithkline Beecham).

Compounds of formula II, (preferred compounds of the present invention),wherein R₃₁₀ is C₁₋₄ alkyl and A₁₉₀ is oxygen may be prepared byreaction of a compound of formula LXX ##STR63## wherein L is a leavinggroup such as halo and R₃₁₀ is C₁₋₄ alkyl; with a corresponding compoundof formula Het-H, wherein Het is a group of formula xxxviii ##STR64## ina solvent inert to the conditions of the reaction; preferably in thepresence of a base.

Compounds of formula LXX wherein L is halo, for example chloro or bromo,may be prepared by reaction of a compound of formula LXXI ##STR65##wherein R₃₁₀ is C₁₋₄ alkyl; with a halogenating agent such as achlorinating agent, for example benzyltriethylammoniumtetrachloroiodate, or a brominating agent, for exampleN-bromosuccinimide, in a solvent inert to the conditions of thereaction.

Compounds of formula LXXI may be prepared by reacting a compound offormula LXXII ##STR66## wherein Hal is halo, suitably bromo or iodo andR₃₁₀ is C₁₋₄ alkyl; with a compound of formula LXXIII ##STR67## whereinQ₅₀ represents a boronic acid group of formula --B(OH)₂ or atrialkylstannyl group of formula --Sn(Alk)₃ (wherein Alk represents aC₁₋₄ alkyl group); in a solvent inert to the conditions of the reaction;preferably by reaction in the presence of a base, such as sodiumcarbonate; suitably in the presence of a metal catalyst, such as apalladium(0) or nickel(0) catalyst.

Compounds of formula LXXIII are well known in the art.

Compounds of formula LXXII may be prepared by reacting a compound offormula LXXIV ##STR68## wherein R₃₁₀ is C₁₋₄ alkyl and T is atrialkylstannyl group of formula --Sn(Alk)₃ wherein Alk represents aC₁₋₄ alkyl group, (suitably a butyl group); with a compound of formulaLXXV ##STR69## wherein Hal is bromo or iodo, suitably bromo in a solventinert to the conditions of the reaction, suitably in the presence of ametal catalyst, such as a palladium(0) or nickel(0) catalyst.

Compounds of formula LXXIV may be prepared as described by Liebeskindand Fengl in Journal of Organic Chemistry (1990) Vol.55 pp 5359/5364.

Compounds of formula LXXV are well-known in the art and are availablecommercially from Lancaster Synthesis Ltd or Aldrich Chemical Co. (UK).

Compounds of formula LXXl may also be prepared by reacting a compound offormula LXXVI ##STR70## wherein Met is lithium or a group of formula MgXwherein X is chloro, bromo or iodo; with a compound of formula LXXVII##STR71## wherein R₃₁₀ is C₁₋₄ alkyl and Alk is C₁₋₄ alkyl; followed byreaction with an acylating agent, for example, with trifluoroaceticanhydride; in a solvent inert to the conditions of the reaction.

Compounds of formula LXXVII are well-known in the art and are availablecommercially from Aldrich Chemical Co. (UK).

Compounds of formula LXXVI may be prepared by reacting a compound offormula LXXVIII ##STR72## wherein Hal is halo, preferably bromo; with aC₁₋₄ alkyl lithium compound or magnesium metal; in a solvent inert tothe conditions of the reaction.

Compounds of formula LXXVIII are described in Gomberg and Pernert (J.Am. Chem. Soc. (1926) Vol 48, p1373) and may be obtained as describedtherein.

They may also be prepared by reacting a compound of formula LXXIIImodified in that Q₅₀ is a group of formula MgHal (wherein Hal is chloro,bromo or iodo) with 1,2-diiodobenzene, 1,2-bromoiodobenzene,1,2-dibromobenzene, or 1,2-bromochlorobenzene (substituted with R₃₁₁ ₁and/or R₃₁₂ groups as appropriate) in a solvent inert to the conditionsof the reaction; in the presence of a palladium(0) or nickel(0)catalyst.

Compounds of formula LXXIII modified in that Q₅₀ is a group of formulaMgHal may be prepared by reacting corresponding compounds wherein Q₅₀ ischloro, bromo or iodo with magnesium metal; in a solvent inert to theconditions of the reaction.

Compounds of formula II wherein A₁₉₀ is oxygen and R₃₁₀ is lower alkylmay also be prepared by reacting a compound of formula LXXIX ##STR73##wherein Het is a group of formula xxxviii above; with a compound offormula LXXIV above, in a solvent inert to the conditions of thereaction, suitably in the presence of a metal catalyst, for example apalladium(0) or nickel(0) catalyst.

Compounds of formula LXXIX may be prepared by reacting a compound offormula LXXX ##STR74## wherein L is a leaving group, suitably halo,(e.g. bromo or chloro); with a compound of the formula Het-H (whereinHet is a group of formula xxxviii above), in a solvent inert to theconditions of the reaction, preferably in the presence of a base.

Compounds of formula LXXX wherein L is bromo or chloro may be preparedby reacting a compound of formula LXXXI ##STR75## with a chlorinatingagent, for example benzyltriethyl-ammonium tetrachloroiodate, or abrominating agent, for example, H-bromosuccinimide.

Compounds of formula LXXXI are known from Hammerschmidt and Vogtle(Chem. Bet. (1979) Vol. 112 p1785) and may be obtained as describedtherein.

Compounds of formula Het-H wherein Het is a group of formula xxxviiiabove wherein R₃₁₆, R₃₁₇ and R₃₁₈ are each independently hydrogen, C₁₋₄alkyl, nitro, fluoro, chloro, bromo, cyano or formyl may be prepared bymethods described in EP-A-0400974 (Merck).

Compounds of formula Het-H wherein Het is a group of formula xxxviiiabove wherein R₃₁₇ is a group of the formula --SO₂ NR₃₂₀ R₃₂₁ may beprepared by reacting a corresponding compound of formula Het-H modifiedin that R₃₁₇ is a sulphonyl chloride group; with an amine of the formulaHNR₃₂₀ R₃₂₁ or a salt thereof; in a solvent inert to the conditions ofthe reaction.

Compounds of formula Het-H wherein Het is a group of formula xxxviiimodified in that R₃₁₇ is a sulphonyl chloride group may be prepared byreacting corresponding compounds of formula Het-H wherein R₃₁₇ is anamino group; with a diazotising agent, such as an alkali metal nitrite,under appropriate conditions (e.g. in the presence of concentratedhydrochloric acid at less than 5° C.); with addition of a source ofcopper (I) ions (e.g. by addition of cuprous chloride) and sulphurdioxide; in a solvent inert to the conditions of the reaction.

Compounds of formula Het-H wherein Het is a group of formula xxxviiiwherein R₃₁₇ is an amino group may be prepared by reducing acorresponding compound wherein R₃₁₇ is a nitro group with a reducingagent, for example hydrogen gas with a catalyst such as a palladiummetal catalyst.

Compounds of formula I modified in that R₅₀ is a group of formula xxxv,xxxvi, or xxxvii above (i.e. so-called `pro-drugs`) may be prepared byreacting an alkali metal salt of a compound of formula I above whereinA₅₁ is oxygen and R₅₀ is hydrogen with compounds of structures xxxv,xxxvi or xxxvii above respectively wherein the free valency shown insaid structures is attached to halo, suitably chloro in a solvent inertto the conditions of the reaction; preferably in the presence of analkali metal iodide, for example potassium iodide.

Compounds of formula I wherein A₅₁ is oxygen and R₅₀ is hydrogen may beprepared by hydrolysis of a compound of formula I wherein A₅₁ is oxygenand R₅₀ is lower alkyl (prepared as described above), for example, byheating under acid or alkaline conditions.

Alternatively, compounds of formula I wherein A₅₁ is oxygen and R₅₀ ishydrogen may be prepared by deprotecting compounds of formula I in whichA₅₁ oxygen modified in that R₅₀ represents a protecting group, forexample:

1) an aralkyl group, by ether cleavage, for example using hydrobromicacid in a liquid inert to the conditions of the reaction;

2) an aralkyl group (for example benzyl or trityl) for example byhydrogenolysis e.g. with hydrogen over palladium on carbon; or

3) a trialkyl silyl group (for example t-butyldimethylsilyl) by methodsof desilylating known to those skilled in the art, for example, byreaction with a source of fluoride, e.g. tetrabutylammonium fluoride).

It will be appreciated by a person skilled in the art that a widevariety of other protecting groups may be used. Examples of suchprotecting groups and methods for their addition and removal can befound in the textbook "Protective Groups in Organic Synthesis" by T. W.Greene, john Wiley & Sons, 1981.

it will also -be appreciated that reactions described above with respectto compounds wherein R₅₀ is C₁₋₄ alkyl may also be carried out by use ofcorresponding compounds modified in that R₅₀ is a protecting group asdescribed above.

In a further aspect, therefore, the present invention provides novelintermediate compounds of the formula XC ##STR76## wherein Z is aprotecting group of the type described above.

Compounds of formula I wherein A₅₀ is sulphur or a group of the formula--NR₅₂ -- may be prepared by reacting a compound of formula XCI##STR77## wherein Hal is halo, suitably bromo or chloro; with a compoundof the formula HSR₅₀ or HNR₅₀ R₅₂ respectively, (or their alkali metalsalts); in a solvent (such as pyridine) inert to the conditions of thereaction. Preferably, where A₅₁ is sulphur, this reaction is followed bytreatment with a strong acid, such as concentrated hydrochloric acid.Any salt formed may be neutralised, if desired, to provide thecorresponding free acid.

Compounds of formula I wherein A is sulphur or a group of formula --NR₅₂-- and R₅₁ is C₁₋₄ alkyl may also be prepared by reaction of a compoundof formula XCI with hydrogen sulphide or ammonia respectively, followedby treatment with an alkylating agent as required.

Compounds of formula XCI may be prepared by reacting a salt, suitably analkali metal salt, of a compound of formula I wherein A₅₁ is oxygen andR₅₀ is hydrogen; with a halogenating agent, suitably a chlorinatingagent such as oxalyl chloride; in a solvent inert to the conditions ofthe reaction.

Compounds of formula I wherein A₅₁ is --NR₅₂ -- wherein R₅₂ is asdefined above may also be prepared by treating a compound of formula Iwherein A₅₀ is oxygen and R₅₀ is C₁₋₄ alkyl with a compound of formulaHNR₅₀ R₅₂ or alkali metal salts thereof, in a solvent inert to theconditions of the reaction.

All novel intermediate compounds herein described containing acyclobutenedione ring are key intermediates in the present invention andform a further aspect of the invention.

Novel intermediates are also provided which correspond to the preferredstructures of formula I above (i.e. structures of formulae II, III andIV, modified in that R₃₁₀ is a protecting group as described above).

Salts of compounds of formula I which are also within the scope of thisinvention may be prepared by conventional means such as by reacting thefree acid or free base forms of the compound of formula I with one ormore equivalents of the appropriate base or acid.

The therapeutic activity of compounds of formula I has been demonstratedby the following tests. In test A the binding affinity of compounds tothe adrenal membrane angiotensin II receptor was determined in vitro andin tests B and C the antihypertensive effect of the compounds wasmeasured in vivo. A detailed description of the tests follows.

Test A

1) Preparation of Membranes

Adrenal glands from male New Zealand white rabbits were homogenised onice in 20 mM aqueous sodium bicarbonate solution containing 50 μM PMSF(phenylmethanesulphonyl fluoride) (2 ml/g wet weight) using a Polytron(Trademark) homogeniser for 3×15 seconds at setting 8. The homogenatewas centrifuged at 900 g for 10 minutes at 4° C. and the pellet wasdiscarded. The supernatant was recentrifuged at 30000 g for 30 minutesat 4° C., and the resulting pellet was resuspended in assay buffer (50mM Tris-HCl, pH 7.4, containing 1 mM EDTA, 6.5 mM MgCl₂, 125 mM NACl, 50μM PMSF, 5 μg/ml pepstatin and 50 μg/ml each of leupeptin, antipain,aprotinin and chymostatin): 10 ml per g original tissue wet weight.Polyethylene glycol was added (final concentration 30%) as acryopreservant and the membrane preparation divided into aliquots andstored at -80° C. until required. Protein was determined by amodification of the method of Lowry (Markwell et al, (1978) Anal.Biochem., 87: 206-210).

2) Binding Assay

Aliquots of rabbit adrenal membranes containing 10-30 μg protein wereincubated with 0.05 nM [¹²⁵ I]angiotensin II in the presence or absenceof potential angiotensin II antagonists in 1 ml polyamide tubes in atotal volume of 200 μI assay buffer. After incubation for 60 minutes am25° C. the reaction was terminated by the addition of ice-cold assaybuffer, and the bound and free radioactivity was separated throughSkatron (Trademark) receptor-binding filters, pre-wetted with assaybuffer, using a Skatron cell harvester. The filters were washed withice-cold phosphate buffered saline, dried, and the trapped radioactivitywas determined using a gamma counter. Non-specific binding, measured inthe presence of 2 μM unlabelled angiotensin II, was subtracted fromtotal binding to obtain specific binding. Radioligand binding curveswere analysed using EBDA and LIGAND (Cambridge Biosoft). Values forbinding affinity were obtained by nonlinear regression analysis ofuntransformed data.

The activities of the compounds described in the Examples givenhereinafter are set out below in Table A, Column 1.

Test B

Female rats, weight range 180-240 g, of the Aoki-Okamoto strain ofspontaneously hypertensive rat were used. The rats in groups of fourwere fasted overnight before administration of the test compound. Bloodpressure was determined in the following way. The rats were placed in acabinet kept at 38° C. with their tails protruding through holes in thecabinet. After 30 minutes in the cabinet blood pressure was measuredusing an inflatable cuff placed round the base of the mail and arterialpulsations monitored with a pneumatic pulse transducer. A pressure,greater than the expected blood pressure, was applied to the cuff, andthis pressure was slowly reduced. The pressure in the cuff at whicharterial pulsations reappeared was taken as the blood pressure. The ratswere removed from the cabinet and each group orally dosed with a givendose of the test compound given as a solution or suspension in 0.25%aqueous carboxymethylcellulose. In addition to the predose reading,blood pressure was measured at 1.5 and 5.0 hours after dosing. Thedegree of blood pressure reduction sufficient to achieve a significancelevel of p<0.01 compared to controls was 9% after correction for controlchanges at appropriate time intervals. Thus, compounds were consideredto be active in this test if they produced a reduction of blood pressureafter correction of 9% or greater than 9%.

Threshold antihypertensive doses of compounds of formula I weredetermined in the following way. Compounds were tested initially at aparticular dose level, for example 90 mg/kg. If the compound wasconsidered sufficiently active (giving a reduction of blood pressureequal to or greater than 16% after correction it was retested at a lowerdose level, for example 30 mg/kg. By testing at successively lower doselevels, a threshold antihypertensive dose (dose giving a reduction ofblood pressure of between 9 and 16% after correction; was determined.Compounds inactive at a particular dose level and giving a reduction ofblood pressure equal to or greater than 16% after correction at the nexthighest dose level were designated as having a thresholdantihypertensive dose within the range covered by the two dose levels.

The activities of the compounds described in the Examples givenhereinafter are set out below in Table A, Column 2.

Test C

The procedure of Test B above was carried out subject to themodification of pretreating the rats with bendrofluazide 10 mg/kg (anorally administered diuretic) at 16 hours and 2 hours prior to the doseof the test compound, to ensure activation of the reninangiotensinsystem.

The activities of the compounds described in the Examples givenhereinafter are set out below in Table A, Column 3.

The antihypertensive activity of the compounds of the present inventionmay also be demonstrated in rats in which the renin-angiotensin systemhas been activated by surgical intervention.

                  TABLE A                                                         ______________________________________                                                               COLUMN 2   COLUMN 3                                                           (Threshold (Threshold                                                         anti-      anti-                                       FINAL                  hypertensive                                                                             hypertensive                                PRODUCT  COLUMN 1 (Ki  dose from  dose from                                   OF       from Test A)  Test B)    Test C)                                     EXAMPLE  (×10.sup.-9 M)                                                                        (mg/kg)    (mg/kg)                                     ______________________________________                                        1        97.6          --         30                                          2        97.6          --         30                                          4        5             0.1        0.1                                         5        1.78          1          1                                           6        400           --         --                                          8        3.19          10         <10                                         9        3.71          10         0.1                                         11       393           --         --                                          12       13.3          --         --                                          13       19            10         <10                                         15       13.5          --         3                                           16       1890          --         --                                          17       21.5          --         --                                          20       81.7          3          1                                           22       3.68          --         30                                          24       11.1          --         3                                           28       27.7          --         10                                          29       13.7          >3         3                                           30       77.9          --         ≦10                                  ______________________________________                                    

The invention is illustrated by the following non-imitative Examples inwhich compositions of mixed solvents are given by volume. Novelcompounds were characterised by one or more of the following: elementalanalysis, nuclear magnetic resonance and infra-red spectroscopy.

Flash chromatography was performed according to the method of Still etal., J. Org. Chem. (1978), Vol. 43, pp 2923-5.

EXAMPLE 1

a) A mixture of 3-isopropoxy-4-tributylstannyl-cyclobut-3-ene-1,2-dione(4.68 g; preparable as described in Liebeskind and Fengl, Journal ofOrganic Chemistry (1990), Vol.55, pp 5359/5364), 1-bromo-2-iodobenzene(3.54 g), dry dimethylformamide (15 ml),tetrakis(triphenylphosphine)palladium(0) (0.606 g) and cuprous iodide(0.196 g) was stirred under a nitrogen atmosphere at ambient temperaturefor approximately 2.5 hours then kept at ambient temperature for 3 days.Diethyl ether (225 ml) was added, and the mixture obtained was washedwith saturated aqueous ammonium chloride (225 ml) and then with 10%aqueous potassium fluoride solution (3×225 ml). The organic phase wasfiltered through a silica bed (5 cm diameter×1 cm depth), and thecollected solids were washed with diethyl ether (50 ml). The resultingorange filtrate and washings were combined and evaporated to give asemi-solid brown oil, which was purified by flash chromatography onsilica gel (loading in dichloromethane and eluting with 20% diethylether in petroleum ether (b.p. 40°-60° C.)) to give the intermediatecompound 3-(2-bromophenyl)-4-isopropoxycyclobut-3-ene-1,2-dione, as ayellow oil (2.16 g).

b) The product from Example 1 (a) above (2.16 g) was dissolved intoluene (170 ml) and to this was added 4-methylbenzeneboronic acid (1.94g), tetrakis-(triphenylphosphine)palladium(0) (0.53 g), ethanol (8.3 ml)and aqueous sodium carbonate solution (2M; 8.3 ml). The resultingmixture was heated under reflux under a nitrogen atmosphere for 3.5hours. The dark reaction mixture obtained was allowed to cool to ambienttemperature then washed with water (2×50 ml). The organic phase wasdried over magnesium sulphate, then evaporated to give a brown oil (3.37g), which was purified by flash chromatography on silica gel (elutingwith dichloromethane), to give a yellow oil (1.48 g). Trituration ofthis oil with i:1 petroleum ether (b.p. 40°-60° C.):diethyl ether gave asuspension of a yellow solid. The solution was removed and the solidresidue obtained was washed with petroleum ether (b.p. 40°-60° C.) anddried in vacuo to give the further intermediate compound3-isopropoxy-4-(4'-methylbiphenyl-2-yl)cyclobut-3-ene-1,2-dione as apale yellow solid (0.96 g; m.p. 126°-30° C.).

c) 3-Isopropoxy-4-(4'-methylbiphenyl-2-yl)cyclobut-3 -ene-1,2-dione(1.24 g; preparable as described in Example 1(b)), carbon tetrachloride(40 ml), recrystallised N-bromosuccinimide (0.79 g) and AIBN(azobis(isobutyronitrile)) (40 mg) were heated together under reflux for4.5 hours. Further AIBN (23 mg) was added and reflux was continued for afurther 4.5 hours. The mixture was kept at ambient temperature forapproximately 16 hours, then cooled briefly ice-water. The resultingyellow supernatant removed. The off-white solid obtained was washed withcold carbon tetrachloride (approx. 3 ml). The resulting yellowsupernatant and washings were combined and evaporated to give a yellowoil which was dried in vacuo to give the further intermediate compound3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxy-cyclobut-3-ene-1,2-dione(1.74 g).

d) 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.66 g; preparable asdescribed in Mantio et al, J. Med. Chem. 34, (1991), pp 2919/2922 and inEP-A-0400914; Merck), and anhydrous potassium carbonate (1.02 g) wereadded to a solution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(1.88 g; preparable as described in Example 1(c)) in drydimethylformamide (10 ml) and the resulting mixture was stirred atambient temperature for approximately 16 hours. More2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.33 g) was added to thedark reaction solution obtained, and stirring was continued at ambienttemperature for an additional 24 hours. The resulting dark mixture waspartitioned between ethyl acetate (100 ml) and water (50 ml). Theorganic layer was then separated, washed with water (50 ml), and driedover magnesium sulphate. The resulting solution was evaporated to leavea dark oil which was purified by flash chromatography on silica gel(eluting with 1% industrial methylated spirit in dichloromethane)followed by flash chromatography on silica gel (eluting with ethylacetate) and flash chromatography on silica gel (eluting with 0% risingto 2% methanol in dichloromethane) to give3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione, an active compound of thepresent invention, as a yellow foam (0.176 g) which melted slowly at 60°C. or above.

EXAMPLE 2

a) A mixture of 1,2-diiodobenzene (6.6 g) andtetrakis(triphenylphosphine)palladium(0) (0.34 g) in AR toluene (100 ml)was stirred under a nitrogen atmosphere at ambient temperature. Asolution of sodium carbonate (2 g) in water (15 ml) was added. Theresulting orange mixture was stirred and heated under reflux while asolution of 4-methylbenzeneboronic acid (1.36 g) in industrialmethylated spirit (40 ml) was added dropwise over a period of 40minutes. The mixture obtained was heated under reflux for an additional4 hours, then cooled to ambient temperature. Aqueous hydrogen peroxide(30%; 1 ml) was added and the resulting mixture was stirred for 1 hourat ambient temperature. Saturated aqueous sodium chloride solution (50ml) was then added and the organic phase was separated. The aqueousphase was extracted with ethyl acetate (2×50 ml) and the combinedorganic phases were washed with saturated aqueous sodium chloridesolution (1×70 ml), dried over magnesium sulphate and evaporated to givean orange oil. This oil was triturated with petroleum ether (b.p.40°-60° C.) (200 ml) to give a gum which was partially purified by flashchromatography on silica gel (eluting with petroleum ether (b.p. 40°-60°C.): ethyl acetate (4:1)) then further purified by high performanceliquid chromatography on a silica column (eluting with petroleum ether(b.p. 60°-80° C.) at 200 ml/minute), to give the intermediate compound2'-iodo-4-methylbiphenyl as a colourless oil (1.3 g).

b) The product from Example 2(a) above (1.23 g) was dissolved in carbontetrachloride (30 ml). N-bromosuccinimide (0.82 g) was added followed byAIBN (33 mg). The mixture obtained was heated under reflux for 4.5 hoursthen kept for approximately 16 hours at ambient temperature. Theresulting pink supernatant solution was removed, and the residual whitesolid obtained was triturated with additional carbon tetrachloride(approx. 3 ml). The supernatant and washings from the trituration werecombined and then evaporated to give the further intermediate compound4-(bromomethyl)-2'-iodobiphenyl as a pink/red oil (1.69 g).

c) 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.731 g) andanhydrous potassium carbonate (1.15 g) were stirred in drydimethylformamide (10 ml) for 10 minutes. A solution of the product ofExample 2(b) (1.65 g) in dry dimethylformamide (10 ml) was addeddropwise, over a period of approximately 5 minutes. The resultingsuspension was stirred at ambient temperature for approximately 16 hoursand then partitioned between diethyl ether (50 ml) and water (50 ml).The layers were separated and the aqueous phase was extracted with morediethyl ether (25 ml). The combined organic phases were then dried overmagnesium sulphate and evaporated to give a brown oil. This oil waspurified by flash chromatography on silica gel (eluting with ethylacetate) and then dried in vacuo to give the further intermediatecompound2-ethyl-3-(2'-iodobiphenyl-4-ylmethyl)-5,7-dimethyl-3H-imidazo[4,5-b]pyridineas a brown oil (1.07 g).

d) A portion of the product from Example 2(c) (97 mg) was dissolved indry dimethyl formamide (1 ml).3-Isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (91 mg) was addedfollowed by tetrakis (triphenylphosphine)palladium(0) (20 mg) and thencuprous iodide (8 mg). After stirring under a nitrogen atmosphere for 70minutes, additional tetrakis(triphenylphosphine)palladium(0) (16 mg) andcuprous iodide (9 mg) were added and stirring was continued am ambienttemperature for an additional 50 minutes. Additional3-isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (41 mg) was addedand stirring was continued for approximately 72 hours. The solution wasthen taken into a combined work up (see "f" below).

e) The remainder of the product of Example 2(c) (0.94 g) was dissolvedin dry dimethylformamide (4 ml) and the solution obtained was stirred atambient temperature under a nitrogen atmosphere as3-isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (1.29 g) followedby tetrakis(triphenylphosphine)palladium(0) (0.143 g) and cuprous iodide(40 mg) were added. The resulting mixture was stirred at ambienttemperature for 5.5 hours. Additionaltetrakis(triphenylphosphine)palladium(0) (0.14 g) and cuprous iodide(0.12 g) were then added. Stirring was continued under nitrogen for 72hours and the resulting solution was then taken into the combinedwork-up (see "f" below).

f) The two red/brown reaction solutions from (d) and (e) above werecombined and diluted with diethyl ether (75 ml) and washed withsaturated aqueous ammonium chloride (50 ml) then 10% aqueous potassiumfluoride solution (3×30 ml) to give a grey solid insoluble material inboth phases. The organic phase was filtered through diatomaceous earth(available under the trade name "Celite") and a small aqueous phase wasremoved. The organic phase was evaporated to give an orange oil whichwas partially purified by flash chromatography on silica gel (elutingwith 0% rising to 4% methanol in dichloromethane). Further purificationwas effected by flash chromatography on silica gel (eluting with diethylether) to give a semi-solid foam which was broken up and dried in vacuoto give3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione,an active compound of the present invention, as a yellow solid, (0.42g), substantially identical to the product of Example 1(d).

EXAMPLE 3

a) To a solution of 1-bromo-2-iodobenzene (200 g) and4-methylbenzeneboronic acid (105 g) in toluene (11) were added sodiumcarbonate (164.8 g), industrial methylated spirit (165 ml), water (165ml) and finally tetrakis(triphenylphosphine)palladium(0) (40.8 g). Themixture obtained was stirred and heated at 95°-100° C. under a nitrogenatmosphere for 18 hours. After cooling to ambient temperature, water(11) was added, and the resulting mixture was stirred for 10 minutes.The organic layer was then separated and dried over magnesium sulphate.The solvent was evaporated under reduced pressure to leave the crudeproduct.

The reaction was repeated as above on 0.45×scale and the crude productsof both reactions were combined and stirred with hexane (11) for 30minutes. Insoluble material was removed by filtration and the solventwas evaporated under reduced pressure. The residue was distilled underreduced pressure through a fractionating column packed with glasshelices to give the intermediate compound 2-bromo-4'-methylbiphenyl(241.7 g) as a colourless oil (b.p. 98°-102° C. at 0.8 mmHg).

b) To a solution of 2-bromo-4'-methylbiphenyl (9.0 g; obtainable asdescribed in Example 3 (a) and in Gomberg and Pernert, J. Am. Chem. Soc.(1926) Vol 48 p 1373) in tetrahydrofuran (60 ml) was added butyllithium(2.5M in hexanes, 15.3 ml) dropwise at -70° C. under a nitrogenatmosphere over a period of 3 minutes. The mixture was stirred for 10minutes at -70° C. then added to a solution of3,4-diisopropoxycyclobut-3-ene-1,2-dione (7.6 g) in tetrahydrofuran (100ml) at -70° C. under nitrogen over a period of 1 minute. The solutionobtained was stirred for an additional 30 minutes at -70° C. thenquenched with trifluoroacetic anhydride (6.4 ml), followed by saturatedaqueous ammonium chloride (40 ml). The resulting mixture was allowed towarm to ambient temperature, then partitioned between diethyl ether (300ml) and aqueous sodium bicarbonate (5%, 300 ml). The aqueous layer wasre-extracted with diethyl ether (200 ml) and the combined organic layerswere washed with brine, dried over magnesium sulphate, and evaporated togive a yellow oily solid which was purified by flash chromatography onsilica gel (eluting with 10% rising to 20% ethyl acetate in petroleumether (b.p. 60°-80° C.)) to give the intermediate compound3-isopropoxy-4-(4'-methylbiphenyl-2-yl)cyclobut-3-ene-1,2-dione as ayellow solid (6.7 g), substantially identical to the product of Example1(b). The above method is described in Reed et al, Journal of OrganicChemistry (1988) Vol.53, p 2477.

It will be appreciated that this intermediate compound may be reacted asdescribed, for example, in Examples 1(c) and 1(d) to provide activecompounds of the present invention, such as the active compound ofExample 1.

EXAMPLE 4

The final products of Examples 1 and 2 (0.35 g), glacial acetic acid(7.5 ml) and water (7.5 ml) were heated together at 95°-100° C. under anitrogen atmosphere for 5 hours. The resulting yellow solution wasfiltered through a cotton wool plug and evaporated to give a glassybrown oil. Trituration of this oil with ethyl acetate (5 ml) gave ayellow solid which was dried in vacuo at 70° C. to provide3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione,an active compound of the present invention (0.23 g; m.p. 245°-247° C.).

EXAMPLE 5

3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]-pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione(1.3 g; preparable as described in Example 4) was suspended in distilledwater (10 ml) and cooled in an ice bath whilst aqueous sodium hydroxidesolution (0.1M; 29 ml) was added dropwise. The resulting mixture wasevaporated under reduced pressure (bath temperature 50° C. or below)giving a brown oil which was triturated with diethyl ether (50 ml) toproduce a yellow solid. This solid was collected and dried in vacuo at60° C. Further trituration of the dried solid with diethyl ether (100ml) and thorough drying in vacuo at 70° C. provided the sodium salt of3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione(1.18 g), an active compound of the present invention. The compoundmelted slowly at 180° C. or above.

EXAMPLE 6

3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(0.44 g; preparable as in Example 2) was stirred in saturated ethanolicammonia solution (10 ml) at ambient temperature for 3 hours and thenkept at ambient temperature for approximately 16 hours. The solvent wasevaporated and the resulting residue was triturated with diethyl etherto give an off-white solid which was dried in vacuo to give3-amino-4-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione(0.25g; m.p. 217° C.), an active compound of the present invention.

EXAMPLE 7

5 7-Dimethyl-2-propyl-3H-imidazo[4,5-b]pyridine (0.69 g) (preparable asdescribed by Mantio et al, J. Med. Chem. 34, (1991), pp 2919/2922 and inEP-A-0400974; Merck) was added to a stirred suspension of sodium hydride(0.15 g; 60% suspension in mineral oil) in dry dimethylformamide (10 ml)over a period of 15 minutes, under a nitrogen atmosphere. Stirring wascontinued for a further 30 minutes. The resulting solution was added toa stirred solution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(1.46 g; preparable as in Example 1(c)) in dry dimethylformamide (10 ml)at 0°-5° C. After stirring for 1 hour at 0°-5° C. the dark solutionobtained was poured into ethyl acetate (75 ml) and the resulting mixturewas washed with water (60 ml). The aqueous phase was then extracted withethyl acetate (60 ml) and the combined organic phases were washed withwater (3×60 ml) and dried over magnesium sulphate. The solvent wasremoved under reduced pressure and the resulting residue was purified byflash chromatography on silica gel (eluting with ethyl acetate/petroleumether (b.p. 40°-60° C.) (4:1)) to give3-[4'-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione,an active compound of the present invention, as a yellow gum (0.73 g).

EXAMPLE 8

A solution of the final product of Example 7 (0.73 g) in a mixture ofacetic acid (38 ml) and water (17 ml) was stirred at 95°-100° C. under anitrogen atmosphere for 18 hours. The solvent was removed under reducedpressure and the resulting residue was triturated with ethyl acetate (20ml) to give 3-[4'-(57-dimethyl-2-propyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione,an active compound of the present invention, as a yellow solid (0.44 9;m.p. 240° C., softening from 210° C.).

EXAMPLE 9

The final product of Example 8 (0.40 g) was dissolved in a mixture ofaqueous sodium hydroxide solution (2.5M; 15 ml) and industrialmethylated spirit (15 ml) and the resulting solution was extracted withdichloromethane (2×15 ml). The combined extracts were dried overmagnesium sulphate and the solvent was evaporated to give the sodiumsalt of3-[4'-(5,7-dimethyl-2-propyl-3H-imidazo[4,5-b]-pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione(0.4 g; m.p. 182° C., with slow decomposition), an active compound ofthe present invention.

EXAMPLE 10

a) 2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (2.17 g) was added tostirred fuming sulphuric acid (7 ml) and the resulting solution waswarmed to 80° C. Potassium nitrate (3.0 g) was added in portions over aperiod of 10 minutes and the resulting mixture was heated am between 95and 100° C. for 10 minutes, cooled, then poured onto ice (approx. 25 g).The mixture was neutralised with concentrated aqueous ammonia solutionand then extracted with dichloromethane (2×50 ml). The combined extractswere dried over magnesium sulphate and the solvent was then evaporated.Recrystallization of the resulting residue from ethyl acetate (15 ml)gave the intermediate compound2-ethyl-5,7-dimethyl-6-nitro-3H-imidazo-[4,5-b]pyridine (1.01 g; m.p.146°-149° C.).

b) A solution of the product of Example 10(a) (1.01 g) in industrialmethylated spirit (75 ml) was shaken in an atmosphere of hydrogen in thepresence of palladium on carbon (10%; 120 mg) at ambient temperature andpressure for 7 hours. The resulting mixture was filtered throughdiatomaceous earth (available under the trade name `Celite`) and thefiltrate was evaporated to leave a viscous pale brown oil. Triturationof this oil with diethyl ether (30 ml) gave the intermediate compound6-amino-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (0.88 g; m.p.153°-155° C.).

c) 6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine (1.89 g;preparable as in Example 10 (b)) was dissolved with stirring in amixture of concentrated hydrochloric acid (2.6 ml) and water (2.6 ml)and cooled to below 5° C. A solution of sodium nitrite (0.76 g) in water(2.2 ml) was then added dropwise, keeping the temperature below 5° C.,to give a solution (A).

Cuprous chloride (0.26 g) was dissolved in a saturated solution ofsulphur dioxide in acetic acid (10 ml) and the resulting solution (B)was cooled to 10° C. Solution (A) was then added to the stirred cooledsolution (B) at 0°-10° C., in portions, over a period of 10 minutes. Theresulting mixture was stirred for 3.5 hours at 10°-15° C., added to ice(100 g) and then extracted with dichloromethane (3×50 ml). The combinedextracts were dried over magnesium sulphate and the solvent wasevaporated to give a pale yellow solid which was added to aqueousdimethylamine solution (30%; 20 ml) at ambient temperature. Theresulting mixture was stirred for 30 minutes. The solvent was thenevaporated under reduced pressure and the residue obtained wastriturated with water (5 ml) to give the intermediate compound2-ethyl-5,7, N,N-tetramethyl-3H-imidazo[4,5-b]pyridine-6-sulphonamide(0.21 g; m.p. 179°-182° C.).

d) Sodium hydride (60% dispersion in mineral oil; 25 mg) was added to asolution of the product of Example 10(c) (0.19 g) in dry dimethylformamide (2 ml) under a nitrogen atmosphere and the resulting mixturewas stirred for 10 minutes. The solution obtained was added dropwise bysyringe at 0°-5° C. to a stirred solution of3-(4'-bromomethylbiphenyl-2-yl)-4 isopropoxycyclobut-3-ene-1,2-dione(0.289 g; preparable as in Example 1 (c)) in dry dimethylformamide (2ml). The resulting mixture was stirred for 1.5 hours at ambienttemperature, poured into ethyl acetate (50 ml), and then washed withwater (2×25 ml). The aqueous washings were then extracted with ethylacetate (40 ml). The combined organic solutions were dried overmagnesium sulphate and the solvent was evaporated under reducedpressure. The resulting residue was purified by flash chromatography onsilica gel (eluting with ethyl acetate/petroleum ether (b.p. 40°-60° C.)(4:1)) to give 2-ethyl-3-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-5,7,N,N-tetramethyl-3H-imidazo[4,5-b]pyridine-6-sulphonamide(0.2 g; m.p. 80° C., with slow decomposition), an active compound of thepresent invention.

EXAMPLE 11

A solution of the final product of Example 10 (0.19 g) in a mixture ofacetic acid (8.3 ml) and water (3.7 mi) was heated at 95°-100° C. for 15hours. The solvent was removed by evaporation under reduced pressure andthe resulting residue was triturated with ethyl acetate (5 ml). Thesolid obtained was collected and dried in vacuo at 70° C. to give2-ethyl-3-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-5,7,N,N-tetramethyl-3H-imidazo[4,5-b]pyridine-6-sulphonamide mono-ethylacetate solvate (0.15 g; m.p. 195°-197° C. (with decomposition)), anactive compound of the present invention.

EXAMPLE 12

a) 6-Amino-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]-pyridine (0.85 g;preparable as in Example 10(b)) was dissolved with stirring in a mixtureof concentrated hydrochloric acid (1.15 ml) and water (1.15 ml) and theresulting solution was cooled to 0° C. A solution of sodium nitrite(0.34 g) in water (1 ml) was added, dropwise, keeping the internaltemperature below 5° C. The resulting solution was stirred at thistemperature for 10 minutes and then added to a stirred solution ofcuprous chloride (0.48 g) in concentrated hydrochloric acid (t.7 ml)keeping the temperature below 10° C. The mixture obtained was stirred at70° C. for 2 hours and then cooled to ambient temperature. A precipitatewas collected and washed with water (5 ml). Recrystallisation of thisprecipitate from methanol (7.5 ml) gave the intermediate compound6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyridine hydrochloride(0.21 g; m.p. 284°-287° C. with decomposition). When left for 18 hoursthe reaction mixture yielded a further quantity of precipitate, whichwas collected by filtration and recrystallised from methanol to give asecond crop (70 mg) of the intermediate compound identified above.

b) Sodium hydride (60% dispersion in mineral oil; 91 rag) was added to asuspension of the product of Example 12(a) (0.28 g) in drydimethylformamide (4 ml) and the resulting mixture was stirred atambient temperature under a nitrogen atmosphere for 30 minutes. Themixture obtained was then added dropwise at ambient temperature to asolution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(0.548 g; preparable as described in Example 1(c)) in drydimethylformamide (5 ml). The resulting mixture was stirred at ambienttemperature for 5 hours and then poured into ethyl acetate (70 ml). Theresulting mixture was washed with water (2×25 ml) and the aqueouswashings were extracted with ethyl acetate (20 ml). The combined organicphases were dried over magnesium sulphate and the solvent was evaporatedunder reduced pressure to give the intermediate compound3-[4'-(6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dioneas a viscous oil (0.65 g).

c) The product of Example 12(b) (0.65 g) was heated for 18 hours am95°-100° C. in a mixture of acetic acid (7 ml and water (2.5 ml) under anitrogen atmosphere. The solvents were evaporated under reduced pressureand the resulting residue was triturated with ethyl acetate (20 ml) toleave a gum. Aqueous sodium hydroxide solution (2.5M; 5 ml) was added tothe gum. The resulting suspension was acidified with concentratedhydrochloric acid to give a yellow solid which was collected byfiltration and purified by flash chromatography on silica gel (elutingwith ethyl acetate/industrial methylated spirit (7:3)) to give3-[4'-(6-chloro-2-ethyl-5,7-dimethyl-3H-imidazo-[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxy-cyclobut-3-ene-1,2-dionehydrochloride, an active compound of the present invention, as a yellowsolid (70 mg; m.p. 205° C. with decomposition).

EXAMPLE 13

Chloromethyl pivalate (3.22 g) was added, dropwise, at ambienttemperature, to a stirring suspension of3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione (4.21 g; preparable as inExample 4) in dry N,N-dimethylacetamide (40 ml). Potassium iodide (2.5g) was added to the resulting mixture and stirring was continued amambient temperature for 2 days. More chloromethyl pivalate (3.7 g) wasadded and stirring was continued for an additional 2 days. The mixtureobtained was poured into diethyl ether (500 ml) to give a gum which wasseparated and then dissolved in a mixture of acetone (100 ml) and ethylacetate (300 ml). The resulting solution was washed with saturatedaqueous sodium bicarbonate solution (2×400 ml) then water (2×400 ml) anddried over magnesium sulphate. The solvents were evaporated underreduced pressure and the residue obtained was purified by flashchromatography on silica gel (eluting with ethyl acetate) to give2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxymethylpivalate, an active compound of the present invention, as a fellow foam(0.54 g) which melted slowly at 60°-80° C.

EXAMPLE 14

To a stirred solution of 4-ethyl-2-propyl-1H-imidazole-5-carboxaldehyde(0.15 g; preparable as described in WO92/00977; Dupont) in drydimethylformamide (3 ml) was added sodium hydride (60% dispersion inmineral oil; 36 mg) and stirring was continued for approximately 45minutes. The resulting solution was then added via canula to a stirredsolution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(0.35 g; preparable as in Example 1(c)) in dry dimethylformamide (3 ml).After stirring for 1 hour, 2-propanol (0.1 ml) was added. The mixtureobtained was poured into ethyl acetate (20 ml) then washed with water(15 ml). The aqueous washings were extracted with ethyl acetate (10 ml)and the combined organic phases were washed with water (5×15 ml) anddried over magnesium sulphate. The solvent was removed under reducedpressure and the residue obtained was purified by flash chromatographyon silica gel (eluting with ethyl acetate/petroleum ether (b.p. 60°-80°C.) (75:25)) to give4-ethyl-1-[2'-(3,4-dioxo-2-isopropoxycyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde,an active compound of the present invention, as a foam (0.194 g).

EXAMPLE 15

The product of Example 14 (0.19 g), acetic acid (2 ml) and water (2 ml)were heated together at 95°-100° C. for approximately 5 hours under anitrogen atmosphere then left at ambient temperature for approximately17 hours. The solvents were removed under reduced pressure and theresulting residue was triturated with ethyl acetate (2×15 ml) and thendried in vacuo at 80° C. to give4-ethyl-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-2-propyl-1H-imidazole-5-carboxaldehyde, an active compound ofthe present invention, as a yellow solid (0.12 g; m.p. 241°-245° C.).

EXAMPLE 16

The final product of Example 5 (0.463 g; dried before use by heating invacuo as the compound appeared to be hygroscopic) was dissolved in drydimethylformamide (3 ml). To the resulting solution was added a solutionof chloromethyl pivalate (0.19 g) in dry dimethylformamide (3 ml). Afterstirring the resulting mixture for approximately 17 hours, potassiumiodide (21 mg) was added and stirring was continued for approximately 3days. More chloromethyl pivalate (98 mg) was added and stirring wascontinued for a further 4 days. The solution obtained was thenpartitioned between water (25 ml) and diethyl ether (25 ml). The aqueouslayer was separated and extracted with diethyl ether (2×25 ml). Thecombined organic layers were dried over magnesium sulphate, the solventwas distilled off and the resulting residue was then purified by flashchromatography on silica gel (eluting with ethyl acetate followed byethyl acetate/industrial methylated spirit (9:1)). The fractionscontaining the slower running of the two main products were combined andevaporated under reduced pressure. The resulting residue was trituratedwith diethyl ether (2 ml) to give a solid which was collected and washedwith diethyl ether (1 ml) and then dried to give3-dimethylamino-4-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo-[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]cyclobut-3-ene-1,2-dione,an active compound of the present invention, as a colourless solid (34mg; m.p. 140°-142° C.).

EXAMPLE 17

The final product of Example 4 (1.01 g; dried before use by heating invacuo as the compound appeared to be hygroscopic) was suspended in dry.N,N-dimethylacetamide (10 ml). The resulting suspension was stirredwhilst 1-chloroethyl pivalate (0.90 g; preparable as described in J.Med. Chem. (1978), Vol. 21, p 753) followed by potassium iodide (0.77 g)were added. Stirring was continued at ambient temperature forapproximately 3 days. The suspension obtained was then diluted withethyl acetate (50 ml) and washed with aqueous sodium bicarbonatesolution (5%; 50 ml) and then water (4×50 ml). The organic layer wasdried over magnesium sulphate, the organic solvents were removed underreduced pressure and the resulting residue was purified by flashchromatography on silica gel (eluting with ethyl acetate) to give1-[2-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-3,4-dioxocyclobut-1-en-1-yloxy]ethylpivalate 0.22 ethyl acetate solvate (0.55g), an active compound of thepresent invention, as a yellow foam which softened and slowly melted atand above 80° C.

EXAMPLE 18

a) A solution of 4-bromomethyl-2'-iodobiphenyl (4.0 g; preparable as inExample 2(b)) and butylamine (40 ml) in dry tetrahydrofuran (55 ml) wasstirred for 18 hours an ambient temperature then boiled under reflux for45 minutes. The solvent was evaporated under reduced pressure and theresulting residue was then dissolved in dichloromethane (100 ml) to givea solution which was washed with aqueous potassium hydroxide solution(1M; 2×50 ml), water (50 ml), then hydrochloric acid (5M; 2×50 ml), thenorganic layer was dried over magnesium sulphate and the organic solventwas evaporated. The residue obtained was purified by flashchromatography on silica gel (eluting with dichloromethane/methanol(9:1) to give the intermediate compoundN-(2'-iodobiphenyl-4ylmethyl)butylamine (1.9 g; m.p. 134°-136° C.).

b) A solution of ethyl 4-chloropyrimidine-5-carboxylate (0.9 g;preparable as described in Bredereck et al., Chem. Ber. (1962), Vol. 95,p 803) in dry tetrahydrofuran (2 ml) was added to a solution of theproduct of Example 18(a) (1.9 g) and triethylamine (2.5 ml) in drytetrahydrofuran (10 ml) and the resulting mixture was stirred at ambienttemperature for approximately 1.5 hours. The solvent was evaporatedunder reduced pressure to give a residue which was dissolved indichloromethane (50 ml), washed with saturated aqueous sodiumbicarbonate solution (2×25 ml), and then dried over magnesium sulphate.The solvent was evaporated and the residue obtained was purified byflash chromatography on silica gel (eluting with ethyl acetate) to givethe intermediate compound ethyl4-[N-butyl-N-(2'-iodobiphenyl-4-ylmethyl)amino]pyrimidine-5-carboxylateas a viscous oil (1.5 g).

c) 3-Isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (1.626 g),tetrakis(triphenylphosphine)palladium(0) (0,348 g), cuprous iodide(0.138 g) and the product from Example 18(b) (1.3 g) were stirredtogether in dry dimethylformamide (20 ml) at ambient temperature under anitrogen atmosphere for 23.5 hours. After dilution with ether (100 ml)the mixture was washed with saturated aqueous ammonium chloride solution(2×25 ml), aqueous potassium fluoride solution (10%; 2×25 ml) and water(2×25 ml). The organic phase was dried over magnesium sulphate and thesolvent was evaporated under reduced pressure to leave a brown solid.This solid was purified by flash chromatography on silica gel (elutingwith petroleum ether (b.p. 40°-60° C.)/ethyl acetate (1:1)) to giveethyl4-[N-butyl-N-[2'-(2-isopropoxy-3,4-dioxo-cyclobut-1-en-1-yl)biphenyl-4-ylmethyl]amino]-pyrimidine-5-carboxylate,an active compound of the present invention, as a yellow oil (0.77 g).

EXAMPLE 19

The product of Example 18(c) (0.67 g) was heated in a mixture of aceticacid (30 ml) and water (15 ml) at 95°-100° C. under a nitrogenatmosphere for 22 hours. The resulting solution was cooled and filtered.The solvents were then evaporated under reduced pressure to give ethyl4-[N-butyl-N-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]amino]pyrimidine-5-carboxylate,an active compound of the present invention, as a brown solid (0.59 g;m.p. 95° C. (dec)).

EXAMPLE 20

A solution of the final product of Example 19 (0.59 g) and sodiumhydroxide (0.51 g) in a mixture of methanol (20 ml) and water (6 ml) wasstirred for 7 hours at ambient temperature. The stirred solution waskept for 18 hours at ambient temperature and then acidified to Ph 2 byaddition of concentrated hydrochloric acid. The resulting mixture wasdiluted with water (20 ml) and filtered to give a solid product (400mg). This solid was then stirred in a solution of sodium hydroxide (0.5g) in water (10 ml) for 6 hours at ambient temperature and the resultingmixture was acidified to Ph 2 with concentrated hydrochloric acid togive a pale brown precipitate This precipitate was collected and driedto give 4-[N-butyl-N-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]amino]pyrimidine-5-carboxylicacid 0.6 hydrochloride (0.2 g; m.p. 172°-175° C. (dec)), an activecompound of the present invention.

EXAMPLE 21

Sodium hydride (60% dispersion in mineral oil; 0. 804 g) was added inportions over a period of 15 minutes at ambient temperature to a stirredsolution of 2-butyl-2-imidazoline-4-spirocyclopentan-5(1H)-one (3.9 g;preparable as described in WO 91/14679; Sanofi) in dry dimethylformamide(68.5 ml) under a nitrogen atmosphere. Stirring was continued for 45minutes. The resulting solution was then added co a stirred solution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(11.17 g; preparable as described in Example 1 (c)) in drydimethylformamide (68.5 ml) and stirring was continued for 2 hours.2-Propanol (2.6 ml) was added and the resulting mixture was poured ontoethyl acetate (450 ml) and then washed with water (250 ml). The aqueouslayer was separated and extracted with ethyl acetate (300 ml). Thecombined organic phases were washed with brine (5×200 ml) and then driedover magnesium sulphate. The organic solvent was evaporated underreduced pressure and the resulting residue was purified by flashchromatography on silica gel (eluting with ethyl acetate/petroleum ether(b.p. 60°-80° C.) (7:3)) to give3-[4'-(2-butyl-5-oxo-2-imidazoline-4-spirocyclopent-1-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione,an active compound of the present invention, as a yellow gum (3.6 g).

EXAMPLE 22

A mixture of the product of Example 21 (3.6 g), acetic acid (35.2 ml)and water (35.2 ml) was heated at 95°-100° C. under a nitrogenatmosphere for approximately 4.5 hours. The solvents were evaporatedunder reduced pressure to leave a gum which was triturated with ethylacetate (2×90 ml) and then dried in vacuo at 60° C. to give3-[4'-(2-butyl-5-oxo-2-imidazoline-4-spirocyclopent-1-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione(1.9l g; m.p. 197°-199° C.), an active compound of the presentinvention.

EXAMPLE 23

a) A solution of 4-(bromomethyl)-2'-iodobiphenyl (9.23 g; preparable asdescribed in Example 2(b)) in dry dimethylformamide (50 ml) was added toa stirring mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde(preparable as described in Drugs of the Future (1991), Vol. 16, p 305),anhydrous potassium carbonate (6.9 g) and dry dimethylformamide (100ml), at ambient temperature. Stirring was continued at ambienttemperature for 24 hours. Water (200 ml) was added and the resultingmixture was extracted with diethyl ether (500 ml then 200 ml). Thecombined extracts were washed with water (2×100 ml) and dried overmagnesium sulphate. The organic solvent was evaporated and the residualorange oil was purified by flash chromatography on silica gel (elutingwith 5% then 30% ethyl acetate in petroleum ether (b.p. 60°-80° C.)) togive the intermediate compound2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazol-5-carboxaldehydeas a yellow oil (8.06 g).

b) 3-Isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.67 g;preparable as described in Liebeskind & Fengl, journal of OrganicChemistry (1990), Vol. 55, pp 5359/5364)),tetrakis(triphenylphosphine)palladium(0) (0.145 g) and cuprous iodide(48 mg) were added to a solution of the product of Example 23(a) (0.5 g)in dry dimethylformamide (5 ml) and the mixture obtained was stirredunder a nitrogen atmosphere at ambient temperature for 24 hours. Diethylether (50 ml) was added and the resulting mixture was washed withsaturated aqueous ammonium chloride (35 ml) then aqueous potassiumfluoride solution (10%; 3×20 ml) and the organic solution was dried overmagnesium sulphate. The organic solvents were evaporated in vacuo andthe residual orange/brown oil was purified by flash chromatography onsilica gel (eluting with 20% ethyl acetate in petroleum ether (b.p.60°-80° C.)) to give2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxaldehyde,an active compound of the present invention, as a partially solidifiedyellow oil (0.22 g).

EXAMPLE 24

A solution of the final product of Example 23 (0.20 g) in a mixture ofglacial acetic acid (5 ml) and water (5 ml) was heated at 95°-100° C.for 4.5 hours. More glacial acetic acid (2 ml) and water (2 ml) wereadded and heating was continued for a further 5 hours. The resultingsolution was then cooled to ambient temperature and filtered. Thesolvents were then evaporated in vacuo to give2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxaldehyde,an active compound of the present invention, as a yellow solid (0.16 g)which softened and melted at or above 50° C.

EXAMPLE 25

a) Sodium borohydride (39 mg) was added at ambient temperature to asolution of the product of Example 23(a) (0.5 g) in methanol (5 ml) andthe resulting solution was stirred for 1.5 hours. The solvent wasevaporated in vacuo and water (50 ml) was added to the resultingresidue. The mixture obtained was extracted with ethyl acetate (2×50 ml)and the combined extracts w(re dried over magnesium sulphate. Thesolvent was evaporated in vacuo to give the intermediate compound2-butyl-4-chloro-5-hydroxymethyl-1-[2'-iodobiphenyl-4-ylmethyl]-1H-imidazoleas a yellow oil (0.33 g).

b) 3-Isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.402 g),tetrakis(triphenylphosphine)palladium(0) (86 mg) and cuprous iodide (28mg) were added to a solution of the product from Example 25(a) above(0.30 g) in dry dimethylformamide (5 ml) at ambient temperature under anitrogen atmosphere. The mixture obtained was stirred for 40 hours.Diethyl ether (50 ml) was added and the resulting mixture was washedwith saturated aqueous ammonium chloride solution (30 ml) then aqueouspotassium fluoride solution (10%; 2×20 ml). The organic solution wasdried over magnesium sulphate and the solvents were evaporated in vacuo.The residual orange oil was dissolved in ethyl acetate (10 ml).Insoluble material was removed by filtration and the solvent wasevaporated in vacuo. The residue obtained was then dissolved in diethylether (10 ml), insoluble material was again removed by filtration andthe solvent was again evaporated in vacuo. The residue obtained waspurified by flash chromatography on silica gel (eluting with ethylacetate/petroleum ether (b.p. 60°-80° C.) (1:1)) to give3-[4'-(2-butyl-4-chloro-5-hydroxymethyl-1H-imidazol-1-ylmethyl)biphenyl-2-yl]-4-isopropoxycyclobut-3-ene-1,2-dione,an active compound of the present invention, as a yellow oil (80 mg).

EXAMPLE 26

Methyl 2-butyl-4-chloro-1H-imidazole-5-carboxylate (0.19 g) was added toa stirring suspension of sodium hydride (60% dispersion in mineral oil;35 mg) in dry dimethylformamide (2 ml) at ambient temperature under anitrogen atmosphere and stirring was continued for 30 minutes. Asolution of3-(4'-bromomethylbiphenyl-2-yl)-4-isopropoxycyclobut-3-ene-1,2-dione(0.64 g; preparable as in Example 1(c)) in dry dimethyl formamide (3 ml)was added and stirring was continued for 24 hours. The reaction mixturewas partitioned between water (20 ml) and diethyl ether (20 ml), and theaqueous layer was separated and extracted with diethyl ether (20 ml).The combined ether solutions were dried over magnesium sulphate and thesolvent was evaporated in vacuo. The residue obtained was purified byflash chromatography on silica gel (eluting with 20% ethyl acetate inpetroleum ether (b.p. 40°-60° C.)) to give methyl2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate,an active compound of the present invention, as a yellow oil (0.17 g).

EXAMPLE 27

a) A solution of the product of Example 23(a) (0.5 g) in t-butanol(18.75 ml) was added to a solution of sodium chlorite (1.02 g) andsodium dihydrogen phosphate (1.02 g) in water (24 ml) at ambienttemperature and the resulting mixture was stirred vigorously for 40hours. Sodium metabisulphite was added until the yellow colour of thesolution was discharged, then most of the solvents were evaporated invacuo. Water (75 ml) was added to the resulting residue and the mixtureobtained was extracted with dichloromethane (2×50 ml). The combinedextracts were dried over magnesium sulphate and the organic solvent wasevaporated in vacuo. Trituration of the resulting residue with diethylether (5 ml) gave the intermediate compound 2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1H-imidazole-5-carboxylic acidas a colourless solid (0.27 g; m.p. 175° C.).

b)2-Butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-l1H-imidazole-5-carboxylicacid (0.43 g; preparable as described in Example 27(a)) was added to astirring suspension of sodium hydride (60% dispersion in mineral oil; 41mg) in dry dimethylformamide (5 ml) at ambient temperature under anitrogen atmosphere, and stirring was continued for 30 minutes.Iodomethane (0.06 ml) was added and stirring was continued for 2 hours.Diethyl ether (20 ml) was added and the mixture obtained was washed withwater (20 ml). The aqueous washings were extracted with diethyl ether(2×20 ml) and the combined organic phases were dried over magnesiumsulphate. The organic solvent was then evaporated to give the furtherintermediate compound methyl2-butyl-4-chloro-1-(2'-iodobiphenyl-4-ylmethyl)-1-imidazole-5-carboxylateas an oil (0.43 g).

c) 3-Isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.53 g),tetrakis(triphenylphosphine)palladium(0) (0.12 g), and cuprous iodide(38 mg) were added to a solution of the product of Example 27(b) (0.42g) in dry dimethylformamide at ambient temperature under a nitrogenatmosphere. The mixture was stirred for 18 hours. Diethyl ether (30 ml)was added and the resulting mixture was washed with saturated aqueousammonium chloride solution (20 ml) followed by aqueous potassiumfluoride solution (10%; 2×20 ml). The organic phase was dried overmagnesium sulphate and the solvent was evaporated in vacuo. The residueobtained was purified by flash chromatography on silica gel (elutingwith 20% rising to 50% ethyl acetate in petroleum ether (b.p. 40°-60°C.)) to give methyl2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxo-cyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate,an active compound of the present invention (substantially identical tothe product of Example 26), as a yellow oil (0.1 g).

EXAMPLE 28

Methyl2-butyl-4-chloro-1-[2'-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate(0.26 g; preparable as described in Example 27(c)) was heated in amixture of glacial acetic acid (5 ml) and water (5 ml) at 95°-100° C.for 5 hours. The solvents were evaporated in vacuo and the residueobtained was purified by flash chromatography on silica gel (elutingwith 10% rising to 30% industrial methylated spirit in ethyl acetate) togive methyl2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxo-cyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylate,an active compound of the present invention, as a yellow oil (0.1 g).

EXAMPLE 29

Aqueous sodium hydroxide solution (2M; 1 ml) was added to a solution ofthe product of Example 28 (90 mg) in methanol (3 ml) at ambienttemperature. The resulting mixture was then stirred for 2 hours. Thesolvent was removed by evaporation in vacuo, and water (2 ml) was addedto the residue obtained, followed by sufficient hydrochloric acid (5M)to adjust the resulting solution to pH 1. The resulting yellowprecipitate was filtered, washed with water and dried to give2-butyl-4-chloro-1-[2'-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)biphenyl-4-ylmethyl]-1H-imidazole-5-carboxylicacid 0.4 hydrochloride, an active compound of the present invention, asa pale yellow solid (70 mg; m.p. 168° C.).

EXAMPLE 30

a) A mixture of 2-butyl-4-chloro-1H-imidazole-5-carboxaldehyde (4.0 g;preparable as described in Drugs of the Future (1991), Vol. 16, p 305),potassium carbonate (2.94 g) and dry dimethylformamide (50 ml) wasstirred for 15 minutes at ambient temperature. 4-Iodobenzyl bromide(6.34 g) was added to the resulting mixture and stirring was continuedfor approximately 17 hours. The solvent was then evaporated underreduced pressure at 80° C. Water (200 ml) was added to the resultingresidue which was then extracted with diethyl ether (2×100 ml). Thecombined extracts were washed with water (50 ml) and dried overmagnesium sulphate. The solvent was evaporated. The resulting residuewas purified by flash chromatography on silica gel (eluting withdichloromethane/methanol (80:1)) to give the intermediate compound2-butyl-4-chloro-1-(4-iodobenzyl)-1H-imidazole-5-carboxaldehyde as anoil (6.9 g).

b) A solution of methyl 3-phenylpropanoate (4.03 g) in drytetrahydrofuran (50 ml) was added over 15 minutes to a stirred solutionof lithium diisopropylamide tetrahydrofuran adduct (16.4 ml; 1.5Msolution in cyclohexane) in dry tetrahydrofuran (50 ml) at -70° C. undera nitrogen atmosphere. Stirring was continued at -70° C. forapproximately 1 hour. A solution of the product from Example 30(a) (6.6g) in dry tetrahydrofuran (50 ml) was then added over 15 minutes and theresulting mixture was stirred at -70° C. for 4 hours. The mixture wasallowed to warm to 0° C. and was then poured into saturated aqueousammonium chloride solution (250 ml) and extracted with ethyl acetate(3×150 ml). The combined extracts were washed with brine (50 ml), driedover sodium sulphate and evaporated to dryness under reduced pressure.The resulting residue was triturated with petroleum ether (b.p. 60°-80°C.; 2×100 ml) then further purified by flash chromatography on silicagel (eluting with dichloromethane/methanol (50:1)) to give theintermediate compound methyl2-benzyl-3-[2-butyl-4-chloro-1-(4-iodobenzyl)-1H-imidazol-5-yl]-3-hydroxypropanoate(5.7 g; m.p. 155°-159° C.) as a solid mixture of diastereoisomers.

c) A solution of the product of Example 30(b) (5.7 g), acetic anhydride(11 ml) and 4-dimethylaminopyridine (0.5 g) in dichloromethane (250 ml)was stirred at ambient temperature for approximately 17 hours and thenwashed with saturated aqueous sodium bicarbonate solution (2×300 ml).The organic layer was dried over magnesium sulphate and the solvent wasevaporated. The resulting residue was dissolved in dry toluene (300 ml)and 1,8-diazabicyclo[5.4.0]undec-7-ene (6 ml) was added. The resultingmixture was heated under nitrogen at 95°-100° C. for approximately 8hours and cooled. The solvent was then evaporated under reducedpressure, and the resulting residue was purified by flash chromatographyon silica gel (eluting with dichloromethane/methanol (60:1)) to give theintermediate compound (E)-methyl2-benzyl-3-[2-butyl-4-chloro-1-(4-iodobenzyl)-1H-imidazol-5-yl]propenoateas an oil (3.5 g).

d) A mixture of the product of Example 30 (c) (0.8 g),3-isopropoxy-4-tributylstannylcyclobut-3-ene-1,2-dione (0.9 g),tetrakis(triphenylphosphine)palladium(0) (0.2 g), cuprous iodide (0.1 g)and dry dimethylformamide (5 ml) was stirred at ambient temperatureunder a nitrogen atmosphere for approximately 17 hours. The solvent wasevaporated under reduced pressure and the resulting residue wasdissolved in diethyl ether (150 ml). The solution obtained was washedwith saturated aqueous ammonium chloride solution (50 ml), then withsaturated aqueous potassium fluoride solution (2×50 ml) and then driedover magnesium sulphate. The solvent was evaporated and the residueobtained was purified by flash chromatography on silica gel (elutingwith dichloromethane/methanol (50:1)) to give the intermediate compound(E)-methyl2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl]propenoateas an oil (0.4 g).

e) A mixture of (E)-methyl2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-isopropoxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl]propenoate (1.2 g; preparable as described in Example 30(d)) andaqueous acetic acid (50%; 20 ml) was heated at 95°-100° C. for 6 hours.The solvents were evaporated under reduced pressure and the residueobtained was triturated with diethyl ether (2 ×20 ml). The resultingsolid was dissolved in industrial methylated spirit (20 ml). Aqueoussodium hydroxide solution (0.5M, 22 ml) was added and the resultingmixture was stirred for 1 hour at ambient temperature and neutralisedwith hydrochloric acid (5M). The solvent was evaporated under reducedpressure and the residue obtained was extracted with aqueous sodiumhydroxide solution (1M; 60 ml) and then acidified with hydrochloric acid(5M). The resulting precipitate was collected, washed with water (2×10ml) and then dried to give(E)-2-benzyl-3-[2-butyl-4-chloro-1-[4-(2-hydroxy-3,4-dioxocyclobut-1-en-1-yl)benzyl]-1H-imidazol-5-yl]propenoic acid, an active compound ofthe present invention, as a solid (0.54 g; m.p. 155°-160° C.).

We claim:
 1. A3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof.
 2. The compound accordingto claim 1, wherein said compound is the sodium salt of3-[4'-(2-ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione.3. A pharmaceutical composition comprising the compound according toclaim 1 in combination with a pharmaceutically acceptable carrier ordiluent.
 4. A method of treating hypertension comprising administeringan effective amount of3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dioneor a pharmaceutically acceptable salt thereof, to a human in need ofsuch treatment.
 5. A process for preparing3-[4'-(2-Ethyl-5,7-dimethyl-3H-imidazo[4,5-b]pyrid-3-ylmethyl)biphenyl-2-yl]-4-hydroxycyclobut-3-ene-1,2-dione,comprising hydrolyzing a compound of formula IV: ##STR78## in whichAm₁₉₀ is oxygen and R₃₁₀ is a lower alkyl.